<?xml version="1.0" encoding="utf-8"?>
<!--XBRL document created with Toppan Merrill Bridge  11.2.0.5 -->
<!--Based on XBRL 2.1-->
<!--Created on: 3/31/2026 4:25:34 PM-->
<!--Modified on: 3/31/2026 4:25:34 PM-->
<link:linkbase xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd" xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:xbrli="http://www.xbrl.org/2003/instance" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xbrldt="http://xbrl.org/2005/xbrldt">
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#StatementConsolidatedStatementsOfOperations" roleURI="http://soligenix.com/role/StatementConsolidatedStatementsOfOperations" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#StatementConsolidatedStatementsOfChangesInEquityAndShareholdersEquityDeficit" roleURI="http://soligenix.com/role/StatementConsolidatedStatementsOfChangesInEquityAndShareholdersEquityDeficit" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#StatementConsolidatedStatementsOfCashFlows" roleURI="http://soligenix.com/role/StatementConsolidatedStatementsOfCashFlows" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockTables" roleURI="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockTables" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureNatureOfBusinessDetails" roleURI="http://soligenix.com/role/DisclosureNatureOfBusinessDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureSummaryOfSignificantAccountingPoliciesDetails" roleURI="http://soligenix.com/role/DisclosureSummaryOfSignificantAccountingPoliciesDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureSummaryOfSignificantAccountingPoliciesLossPerShareDetails" roleURI="http://soligenix.com/role/DisclosureSummaryOfSignificantAccountingPoliciesLossPerShareDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureLeasesDetails" roleURI="http://soligenix.com/role/DisclosureLeasesDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureDebtDetails" roleURI="http://soligenix.com/role/DisclosureDebtDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureShareholdersEquityDetails" roleURI="http://soligenix.com/role/DisclosureShareholdersEquityDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockDetails" roleURI="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfSharesAvailableForGrantUnder2025PlanDetails" roleURI="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfSharesAvailableForGrantUnder2025PlanDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfWeightedAverageExercisePriceByPriceRangeForOutstandingOptionsToPurchaseCommonStockDetails" roleURI="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfWeightedAverageExercisePriceByPriceRangeForOutstandingOptionsToPurchaseCommonStockDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfShareBasedCompensationExpenseDetails" roleURI="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfShareBasedCompensationExpenseDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfWarrantActivityDetails" roleURI="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfWarrantActivityDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfRemainingLifeByGrantDateForOutstandingWarrantsDetails" roleURI="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfRemainingLifeByGrantDateForOutstandingWarrantsDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureCommitmentsAndContingenciesDetails" roleURI="http://soligenix.com/role/DisclosureCommitmentsAndContingenciesDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureCommitmentsAndContingenciesMaturityDetails" roleURI="http://soligenix.com/role/DisclosureCommitmentsAndContingenciesMaturityDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureOperatingSegmentsSegmentRevenuesAndProfitLossDetails" roleURI="http://soligenix.com/role/DisclosureOperatingSegmentsSegmentRevenuesAndProfitLossDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureOperatingSegmentsReconciliationToConsolidatedLossBeforeIncomeTaxesDetails" roleURI="http://soligenix.com/role/DisclosureOperatingSegmentsReconciliationToConsolidatedLossBeforeIncomeTaxesDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureOperatingSegmentsSegmentAssetsDetails" roleURI="http://soligenix.com/role/DisclosureOperatingSegmentsSegmentAssetsDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <roleRef xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureSubsequentEventsDetails" roleURI="http://soligenix.com/role/DisclosureSubsequentEventsDetails" xmlns="http://www.xbrl.org/2003/linkbase" />
  <link:roleRef roleURI="http://soligenix.com/role/DisclosureStandardAndCustomAxisDomainDefaults" xlink:type="simple" xlink:href="sngx-20251231.xsd#DisclosureStandardAndCustomAxisDomainDefaults" />
  <link:roleRef roleURI="http://fasb.org/srt/role/srt-eedm/ExtensibleEnumerationLists" xlink:type="simple" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-roles-2024.xsd#eedm1" />
  <link:roleRef roleURI="http://fasb.org/us-gaap/role/eedm/ExtensibleEnumerationLists" xlink:type="simple" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-roles-2024.xsd#eedm" />
  <link:arcroleRef arcroleURI="http://www.esma.europa.eu/xbrl/esef/arcrole/wider-narrower" xlink:type="simple" xlink:href="http://www.xbrl.org/lrr/arcrole/esma-arcrole-2018-11-21.xsd#wider-narrower" />
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-default" />
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#dimension-domain" />
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#hypercube-dimension" />
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/domain-member" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#domain-member" />
  <link:arcroleRef arcroleURI="http://xbrl.org/int/dim/arcrole/all" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#all" />
  <link:definitionLink xlink:type="extended" xlink:role="http://fasb.org/srt/role/srt-eedm/ExtensibleEnumerationLists" xlink:title="SRT Extensible Enumeration Domain Members" />
  <link:definitionLink xlink:type="extended" xlink:role="http://fasb.org/us-gaap/role/eedm/ExtensibleEnumerationLists" xlink:title="Extensible Enumeration Domain Members" />
  <link:definitionLink xlink:type="extended" xlink:role="http://soligenix.com/role/DisclosureStandardAndCustomAxisDomainDefaults">
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementClassOfStockAxis" xlink:label="StatementClassOfStockAxis" xlink:title="StatementClassOfStockAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ClassOfStockDomain" xlink:label="ClassOfStockDomain" xlink:title="ClassOfStockDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="StatementClassOfStockAxis" xlink:to="ClassOfStockDomain" xlink:title="definition: StatementClassOfStockAxis to ClassOfStockDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ProductOrServiceAxis" xlink:label="ProductOrServiceAxis" xlink:title="ProductOrServiceAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ProductsAndServicesDomain" xlink:label="ProductsAndServicesDomain" xlink:title="ProductsAndServicesDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="ProductOrServiceAxis" xlink:to="ProductsAndServicesDomain" xlink:title="definition: ProductOrServiceAxis to ProductsAndServicesDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementEquityComponentsAxis" xlink:label="StatementEquityComponentsAxis" xlink:title="StatementEquityComponentsAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_EquityComponentDomain" xlink:label="EquityComponentDomain" xlink:title="EquityComponentDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="StatementEquityComponentsAxis" xlink:to="EquityComponentDomain" xlink:title="definition: StatementEquityComponentsAxis to EquityComponentDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventTypeAxis" xlink:label="SubsequentEventTypeAxis" xlink:title="SubsequentEventTypeAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventTypeDomain" xlink:label="SubsequentEventTypeDomain" xlink:title="SubsequentEventTypeDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="SubsequentEventTypeAxis" xlink:to="SubsequentEventTypeDomain" xlink:title="definition: SubsequentEventTypeAxis to SubsequentEventTypeDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_TypeOfArrangementAxis" xlink:label="TypeOfArrangementAxis" xlink:title="TypeOfArrangementAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ArrangementsAndNonarrangementTransactionsMember" xlink:label="ArrangementsAndNonarrangementTransactionsMember" xlink:title="ArrangementsAndNonarrangementTransactionsMember" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="TypeOfArrangementAxis" xlink:to="ArrangementsAndNonarrangementTransactionsMember" xlink:title="definition: TypeOfArrangementAxis to ArrangementsAndNonarrangementTransactionsMember" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_CounterpartyNameAxis" xlink:label="CounterpartyNameAxis" xlink:title="CounterpartyNameAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_RepurchaseAgreementCounterpartyNameDomain" xlink:label="RepurchaseAgreementCounterpartyNameDomain" xlink:title="RepurchaseAgreementCounterpartyNameDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="CounterpartyNameAxis" xlink:to="RepurchaseAgreementCounterpartyNameDomain" xlink:title="definition: CounterpartyNameAxis to RepurchaseAgreementCounterpartyNameDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongtermDebtTypeAxis" xlink:label="LongtermDebtTypeAxis" xlink:title="LongtermDebtTypeAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongtermDebtTypeDomain" xlink:label="LongtermDebtTypeDomain" xlink:title="LongtermDebtTypeDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="LongtermDebtTypeAxis" xlink:to="LongtermDebtTypeDomain" xlink:title="definition: LongtermDebtTypeAxis to LongtermDebtTypeDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CreditFacilityAxis" xlink:label="CreditFacilityAxis" xlink:title="CreditFacilityAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CreditFacilityDomain" xlink:label="CreditFacilityDomain" xlink:title="CreditFacilityDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="CreditFacilityAxis" xlink:to="CreditFacilityDomain" xlink:title="definition: CreditFacilityAxis to CreditFacilityDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DebtInstrumentAxis" xlink:label="DebtInstrumentAxis" xlink:title="DebtInstrumentAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DebtInstrumentNameDomain" xlink:label="DebtInstrumentNameDomain" xlink:title="DebtInstrumentNameDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="DebtInstrumentAxis" xlink:to="DebtInstrumentNameDomain" xlink:title="definition: DebtInstrumentAxis to DebtInstrumentNameDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_FiniteLivedIntangibleAssetsByMajorClassAxis" xlink:label="FiniteLivedIntangibleAssetsByMajorClassAxis" xlink:title="FiniteLivedIntangibleAssetsByMajorClassAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:label="FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:title="FiniteLivedIntangibleAssetsMajorClassNameDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="FiniteLivedIntangibleAssetsByMajorClassAxis" xlink:to="FiniteLivedIntangibleAssetsMajorClassNameDomain" xlink:title="definition: FiniteLivedIntangibleAssetsByMajorClassAxis to FiniteLivedIntangibleAssetsMajorClassNameDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_TitleOfIndividualAxis" xlink:label="TitleOfIndividualAxis" xlink:title="TitleOfIndividualAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_TitleOfIndividualWithRelationshipToEntityDomain" xlink:label="TitleOfIndividualWithRelationshipToEntityDomain" xlink:title="TitleOfIndividualWithRelationshipToEntityDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="TitleOfIndividualAxis" xlink:to="TitleOfIndividualWithRelationshipToEntityDomain" xlink:title="definition: TitleOfIndividualAxis to TitleOfIndividualWithRelationshipToEntityDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_OwnershipAxis" xlink:label="OwnershipAxis" xlink:title="OwnershipAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_OwnershipDomain" xlink:label="OwnershipDomain" xlink:title="OwnershipDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="OwnershipAxis" xlink:to="OwnershipDomain" xlink:title="definition: OwnershipAxis to OwnershipDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RestructuringCostAndReserveAxis" xlink:label="RestructuringCostAndReserveAxis" xlink:title="RestructuringCostAndReserveAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_TypeOfRestructuringDomain" xlink:label="TypeOfRestructuringDomain" xlink:title="TypeOfRestructuringDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="RestructuringCostAndReserveAxis" xlink:to="TypeOfRestructuringDomain" xlink:title="definition: RestructuringCostAndReserveAxis to TypeOfRestructuringDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_BalanceSheetLocationAxis" xlink:label="BalanceSheetLocationAxis" xlink:title="BalanceSheetLocationAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_BalanceSheetLocationDomain" xlink:label="BalanceSheetLocationDomain" xlink:title="BalanceSheetLocationDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="BalanceSheetLocationAxis" xlink:to="BalanceSheetLocationDomain" xlink:title="definition: BalanceSheetLocationAxis to BalanceSheetLocationDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AwardTypeAxis" xlink:label="AwardTypeAxis" xlink:title="AwardTypeAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:label="ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:title="ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="AwardTypeAxis" xlink:to="ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:title="definition: AwardTypeAxis to ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_GranteeStatusAxis" xlink:label="GranteeStatusAxis" xlink:title="GranteeStatusAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_GranteeStatusDomain" xlink:label="GranteeStatusDomain" xlink:title="GranteeStatusDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="GranteeStatusAxis" xlink:to="GranteeStatusDomain" xlink:title="definition: GranteeStatusAxis to GranteeStatusDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:label="AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:title="AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AntidilutiveSecuritiesNameDomain" xlink:label="AntidilutiveSecuritiesNameDomain" xlink:title="AntidilutiveSecuritiesNameDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:to="AntidilutiveSecuritiesNameDomain" xlink:title="definition: AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis to AntidilutiveSecuritiesNameDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PropertyPlantAndEquipmentByTypeAxis" xlink:label="PropertyPlantAndEquipmentByTypeAxis" xlink:title="PropertyPlantAndEquipmentByTypeAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PropertyPlantAndEquipmentTypeDomain" xlink:label="PropertyPlantAndEquipmentTypeDomain" xlink:title="PropertyPlantAndEquipmentTypeDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="PropertyPlantAndEquipmentByTypeAxis" xlink:to="PropertyPlantAndEquipmentTypeDomain" xlink:title="definition: PropertyPlantAndEquipmentByTypeAxis to PropertyPlantAndEquipmentTypeDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_StatementScenarioAxis" xlink:label="StatementScenarioAxis" xlink:title="StatementScenarioAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ScenarioUnspecifiedDomain" xlink:label="ScenarioUnspecifiedDomain" xlink:title="ScenarioUnspecifiedDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="StatementScenarioAxis" xlink:to="ScenarioUnspecifiedDomain" xlink:title="definition: StatementScenarioAxis to ScenarioUnspecifiedDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_RangeAxis" xlink:label="RangeAxis" xlink:title="RangeAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_RangeMember" xlink:label="RangeMember" xlink:title="RangeMember" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="RangeAxis" xlink:to="RangeMember" xlink:title="definition: RangeAxis to RangeMember" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RelatedPartyTransactionsByRelatedPartyAxis" xlink:label="RelatedPartyTransactionsByRelatedPartyAxis" xlink:title="RelatedPartyTransactionsByRelatedPartyAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RelatedPartyDomain" xlink:label="RelatedPartyDomain" xlink:title="RelatedPartyDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="RelatedPartyTransactionsByRelatedPartyAxis" xlink:to="RelatedPartyDomain" xlink:title="definition: RelatedPartyTransactionsByRelatedPartyAxis to RelatedPartyDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsidiarySaleOfStockAxis" xlink:label="SubsidiarySaleOfStockAxis" xlink:title="SubsidiarySaleOfStockAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:label="SaleOfStockNameOfTransactionDomain" xlink:title="SaleOfStockNameOfTransactionDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="SubsidiarySaleOfStockAxis" xlink:to="SaleOfStockNameOfTransactionDomain" xlink:title="definition: SubsidiarySaleOfStockAxis to SaleOfStockNameOfTransactionDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2024/dei-2024.xsd#dei_LegalEntityAxis" xlink:label="LegalEntityAxis" xlink:title="LegalEntityAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.sec.gov/dei/2024/dei-2024.xsd#dei_EntityDomain" xlink:label="EntityDomain" xlink:title="EntityDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="LegalEntityAxis" xlink:to="EntityDomain" xlink:title="definition: LegalEntityAxis to EntityDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" xlink:label="LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" xlink:title="LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:label="LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:title="LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" xlink:to="LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:title="definition: LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis to LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementBusinessSegmentsAxis" xlink:label="StatementBusinessSegmentsAxis" xlink:title="StatementBusinessSegmentsAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SegmentDomain" xlink:label="SegmentDomain" xlink:title="SegmentDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="StatementBusinessSegmentsAxis" xlink:to="SegmentDomain" xlink:title="definition: StatementBusinessSegmentsAxis to SegmentDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ConsolidationItemsAxis" xlink:label="ConsolidationItemsAxis" xlink:title="ConsolidationItemsAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ConsolidationItemsDomain" xlink:label="ConsolidationItemsDomain" xlink:title="ConsolidationItemsDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="ConsolidationItemsAxis" xlink:to="ConsolidationItemsDomain" xlink:title="definition: ConsolidationItemsAxis to ConsolidationItemsDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OptionIndexedToIssuersEquityTypeAxis" xlink:label="OptionIndexedToIssuersEquityTypeAxis" xlink:title="OptionIndexedToIssuersEquityTypeAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OptionIndexedToIssuersEquityTypeDomain" xlink:label="OptionIndexedToIssuersEquityTypeDomain" xlink:title="OptionIndexedToIssuersEquityTypeDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="OptionIndexedToIssuersEquityTypeAxis" xlink:to="OptionIndexedToIssuersEquityTypeDomain" xlink:title="definition: OptionIndexedToIssuersEquityTypeAxis to OptionIndexedToIssuersEquityTypeDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxAuthorityAxis" xlink:label="IncomeTaxAuthorityAxis" xlink:title="IncomeTaxAuthorityAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxAuthorityDomain" xlink:label="IncomeTaxAuthorityDomain" xlink:title="IncomeTaxAuthorityDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="IncomeTaxAuthorityAxis" xlink:to="IncomeTaxAuthorityDomain" xlink:title="definition: IncomeTaxAuthorityAxis to IncomeTaxAuthorityDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PlanNameAxis" xlink:label="PlanNameAxis" xlink:title="PlanNameAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PlanNameDomain" xlink:label="PlanNameDomain" xlink:title="PlanNameDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="PlanNameAxis" xlink:to="PlanNameDomain" xlink:title="definition: PlanNameAxis to PlanNameDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:label="ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:title="ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:label="ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:title="ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:to="ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:title="definition: ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis to ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeStatementLocationAxis" xlink:label="IncomeStatementLocationAxis" xlink:title="IncomeStatementLocationAxis" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeStatementLocationDomain" xlink:label="IncomeStatementLocationDomain" xlink:title="IncomeStatementLocationDomain" />
    <link:definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="IncomeStatementLocationAxis" xlink:to="IncomeStatementLocationDomain" xlink:title="definition: IncomeStatementLocationAxis to IncomeStatementLocationDomain" use="optional" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ClassOfWarrantOrRightAxis" xlink:label="us-gaap_ClassOfWarrantOrRightAxis_1" xlink:title="us-gaap_ClassOfWarrantOrRightAxis_1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ClassOfWarrantOrRightDomain" xlink:label="us-gaap_ClassOfWarrantOrRightDomain_1" xlink:title="us-gaap_ClassOfWarrantOrRightDomain_1" />
    <link:definitionArc xlink:type="arc" xlink:from="us-gaap_ClassOfWarrantOrRightAxis_1" xlink:to="us-gaap_ClassOfWarrantOrRightDomain_1" use="optional" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:title="definition:us-gaap_ClassOfWarrantOrRightAxis_1 To us-gaap_ClassOfWarrantOrRightDomain_1" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_MeasurementInputTypeAxis" xlink:label="us-gaap_MeasurementInputTypeAxis_1" xlink:title="us-gaap_MeasurementInputTypeAxis_1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_MeasurementInputTypeDomain" xlink:label="us-gaap_MeasurementInputTypeDomain_1" xlink:title="us-gaap_MeasurementInputTypeDomain_1" />
    <link:definitionArc xlink:type="arc" xlink:from="us-gaap_MeasurementInputTypeAxis_1" xlink:to="us-gaap_MeasurementInputTypeDomain_1" use="optional" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:title="definition:us-gaap_MeasurementInputTypeAxis_1 To us-gaap_MeasurementInputTypeDomain_1" order="1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_RestatementAxis" xlink:label="srt_RestatementAxis_1" xlink:title="srt_RestatementAxis_1" />
    <link:loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_RestatementDomain" xlink:label="srt_RestatementDomain_1" xlink:title="srt_RestatementDomain_1" />
    <link:definitionArc xlink:type="arc" xlink:from="srt_RestatementAxis_1" xlink:to="srt_RestatementDomain_1" use="optional" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:title="definition:srt_RestatementAxis_1 To srt_RestatementDomain_1" order="1" />
  </link:definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/StatementConsolidatedStatementsOfOperations" xlink:type="extended" xlink:title="00200 - Statement - Consolidated Statements of Operations" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementTable" xlink:label="us-gaap_StatementTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ProductOrServiceAxis" xlink:label="srt_ProductOrServiceAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_StatementTable" xlink:to="srt_ProductOrServiceAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ProductsAndServicesDomain" xlink:label="srt_ProductsAndServicesDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_ProductOrServiceAxis" xlink:to="srt_ProductsAndServicesDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_GrantMember" xlink:label="us-gaap_GrantMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_ProductsAndServicesDomain" xlink:to="us-gaap_GrantMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementLineItems" xlink:label="us-gaap_StatementLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StatementTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_Revenues" xlink:label="us-gaap_Revenues" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_Revenues" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CostOfRevenue" xlink:label="us-gaap_CostOfRevenue" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_CostOfRevenue" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_GrossProfit" xlink:label="us-gaap_GrossProfit" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_GrossProfit" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingExpensesAbstract" xlink:label="us-gaap_OperatingExpensesAbstract" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_OperatingExpensesAbstract" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ResearchAndDevelopmentExpense" xlink:label="us-gaap_ResearchAndDevelopmentExpense" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_OperatingExpensesAbstract" xlink:to="us-gaap_ResearchAndDevelopmentExpense" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_GeneralAndAdministrativeExpense" xlink:label="us-gaap_GeneralAndAdministrativeExpense" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_OperatingExpensesAbstract" xlink:to="us-gaap_GeneralAndAdministrativeExpense" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingExpenses" xlink:label="us-gaap_OperatingExpenses" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_OperatingExpenses" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingIncomeLoss" xlink:label="us-gaap_OperatingIncomeLoss" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_OperatingIncomeLoss" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NonoperatingIncomeExpenseAbstract" xlink:label="us-gaap_NonoperatingIncomeExpenseAbstract" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="8" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_NonoperatingIncomeExpenseAbstract" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ForeignCurrencyTransactionGainLossBeforeTax" xlink:label="us-gaap_ForeignCurrencyTransactionGainLossBeforeTax" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_NonoperatingIncomeExpenseAbstract" xlink:to="us-gaap_ForeignCurrencyTransactionGainLossBeforeTax" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_InterestIncomeExpenseNonoperatingNet" xlink:label="us-gaap_InterestIncomeExpenseNonoperatingNet" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_NonoperatingIncomeExpenseAbstract" xlink:to="us-gaap_InterestIncomeExpenseNonoperatingNet" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_UkResearchAndDevelopmentIncentives" xlink:label="sngx_UkResearchAndDevelopmentIncentives" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_NonoperatingIncomeExpenseAbstract" xlink:to="sngx_UkResearchAndDevelopmentIncentives" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_EmployeeRetentionCreditCaresAct" xlink:label="sngx_EmployeeRetentionCreditCaresAct" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_NonoperatingIncomeExpenseAbstract" xlink:to="sngx_EmployeeRetentionCreditCaresAct" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OtherNonoperatingIncome" xlink:label="us-gaap_OtherNonoperatingIncome" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_NonoperatingIncomeExpenseAbstract" xlink:to="us-gaap_OtherNonoperatingIncome" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_FairValueAdjustmentOfConvertibleDebt" xlink:label="sngx_FairValueAdjustmentOfConvertibleDebt" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_NonoperatingIncomeExpenseAbstract" xlink:to="sngx_FairValueAdjustmentOfConvertibleDebt" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NonoperatingIncomeExpense" xlink:label="us-gaap_NonoperatingIncomeExpense" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="us-gaap_NonoperatingIncomeExpenseAbstract" xlink:to="us-gaap_NonoperatingIncomeExpense" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:label="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="9" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxExpenseBenefit" xlink:label="us-gaap_IncomeTaxExpenseBenefit" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="10" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_IncomeTaxExpenseBenefit" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic" xlink:label="us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="11" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_NetIncomeLossAvailableToCommonStockholdersBasic" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_EarningsPerShareBasic" xlink:label="us-gaap_EarningsPerShareBasic" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="12" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_EarningsPerShareBasic" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_EarningsPerShareDiluted" xlink:label="us-gaap_EarningsPerShareDiluted" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="13" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_EarningsPerShareDiluted" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_WeightedAverageNumberOfSharesOutstandingBasic" xlink:label="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="14" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_WeightedAverageNumberOfSharesOutstandingBasic" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding" xlink:label="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="15" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/StatementConsolidatedStatementsOfChangesInEquityAndShareholdersEquityDeficit" xlink:type="extended" xlink:title="00400 - Statement - Consolidated Statements of Changes in Equity and Shareholders' Equity (Deficit)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementTable" xlink:label="us-gaap_StatementTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementEquityComponentsAxis" xlink:label="us-gaap_StatementEquityComponentsAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_StatementEquityComponentsAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_EquityComponentDomain" xlink:label="us-gaap_EquityComponentDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CommonStockMember" xlink:label="us-gaap_CommonStockMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_CommonStockMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AdditionalPaidInCapitalMember" xlink:label="us-gaap_AdditionalPaidInCapitalMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_AdditionalPaidInCapitalMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AccumulatedOtherComprehensiveIncomeMember" xlink:label="us-gaap_AccumulatedOtherComprehensiveIncomeMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_AccumulatedOtherComprehensiveIncomeMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RetainedEarningsMember" xlink:label="us-gaap_RetainedEarningsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_RetainedEarningsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsidiarySaleOfStockAxis" xlink:label="us-gaap_SubsidiarySaleOfStockAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="2" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_SubsidiarySaleOfStockAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PublicOfferingMember" xlink:label="sngx_PublicOfferingMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sngx_PublicOfferingMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_AtMarketIssuanceSalesAgreementMember" xlink:label="sngx_AtMarketIssuanceSalesAgreementMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sngx_AtMarketIssuanceSalesAgreementMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ClassOfWarrantOrRightAxis" xlink:label="us-gaap_ClassOfWarrantOrRightAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="3" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_ClassOfWarrantOrRightAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ClassOfWarrantOrRightDomain" xlink:label="us-gaap_ClassOfWarrantOrRightDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_ClassOfWarrantOrRightAxis" xlink:to="us-gaap_ClassOfWarrantOrRightDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PreFundedWarrantMember" xlink:label="sngx_PreFundedWarrantMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_ClassOfWarrantOrRightDomain" xlink:to="sngx_PreFundedWarrantMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ExistingWarrantsMember" xlink:label="sngx_ExistingWarrantsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_ClassOfWarrantOrRightDomain" xlink:to="sngx_ExistingWarrantsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_NewWarrantsMember" xlink:label="sngx_NewWarrantsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_ClassOfWarrantOrRightDomain" xlink:to="sngx_NewWarrantsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementLineItems" xlink:label="us-gaap_StatementLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StatementTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockholdersEquity" xlink:label="us-gaap_StockholdersEquity" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockholdersEquity" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CommonStockSharesIssued" xlink:label="us-gaap_CommonStockSharesIssued" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_CommonStockSharesIssued" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodValueNewIssues" xlink:label="us-gaap_StockIssuedDuringPeriodValueNewIssues" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodValueNewIssues" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodSharesNewIssues" xlink:label="us-gaap_StockIssuedDuringPeriodSharesNewIssues" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesNewIssues" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AdjustmentsToAdditionalPaidInCapitalStockIssuedIssuanceCosts" xlink:label="us-gaap_AdjustmentsToAdditionalPaidInCapitalStockIssuedIssuanceCosts" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_AdjustmentsToAdditionalPaidInCapitalStockIssuedIssuanceCosts" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockAndPreFundedWarrantsIssuedDuringPeriodValue" xlink:label="sngx_StockAndPreFundedWarrantsIssuedDuringPeriodValue" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="us-gaap_StatementLineItems" xlink:to="sngx_StockAndPreFundedWarrantsIssuedDuringPeriodValue" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockAndPreFundedWarrantsIssuedDuringPeriodShares" xlink:label="sngx_StockAndPreFundedWarrantsIssuedDuringPeriodShares" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="8" xlink:from="us-gaap_StatementLineItems" xlink:to="sngx_StockAndPreFundedWarrantsIssuedDuringPeriodShares" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodValueIssuedForServices" xlink:label="us-gaap_StockIssuedDuringPeriodValueIssuedForServices" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="9" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodValueIssuedForServices" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodSharesIssuedForServices" xlink:label="us-gaap_StockIssuedDuringPeriodSharesIssuedForServices" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="10" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesIssuedForServices" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockIssuedDuringPeriodValueReverseStockSplits" xlink:label="sngx_StockIssuedDuringPeriodValueReverseStockSplits" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="11" xlink:from="us-gaap_StatementLineItems" xlink:to="sngx_StockIssuedDuringPeriodValueReverseStockSplits" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodSharesReverseStockSplits" xlink:label="us-gaap_StockIssuedDuringPeriodSharesReverseStockSplits" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="12" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesReverseStockSplits" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockIssuedDuringPeriodValueExerciseOfWarrants" xlink:label="sngx_StockIssuedDuringPeriodValueExerciseOfWarrants" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="13" xlink:from="us-gaap_StatementLineItems" xlink:to="sngx_StockIssuedDuringPeriodValueExerciseOfWarrants" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockIssuedDuringPeriodShareExerciseOfWarrants" xlink:label="sngx_StockIssuedDuringPeriodShareExerciseOfWarrants" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="14" xlink:from="us-gaap_StatementLineItems" xlink:to="sngx_StockIssuedDuringPeriodShareExerciseOfWarrants" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_AdjustmentsToAdditionalPaidInCapitalWarrantsIssuedIssuanceCosts" xlink:label="sngx_AdjustmentsToAdditionalPaidInCapitalWarrantsIssuedIssuanceCosts" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="15" xlink:from="us-gaap_StatementLineItems" xlink:to="sngx_AdjustmentsToAdditionalPaidInCapitalWarrantsIssuedIssuanceCosts" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AdjustmentsToAdditionalPaidInCapitalWarrantIssued" xlink:label="us-gaap_AdjustmentsToAdditionalPaidInCapitalWarrantIssued" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="16" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_AdjustmentsToAdditionalPaidInCapitalWarrantIssued" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodValueConversionOfConvertibleSecurities" xlink:label="us-gaap_StockIssuedDuringPeriodValueConversionOfConvertibleSecurities" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="17" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodValueConversionOfConvertibleSecurities" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities" xlink:label="us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="18" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" xlink:label="us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="19" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_AdjustmentsToAdditionalPaidInCapitalSharebasedCompensationRequisiteServicePeriodRecognitionValue" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OtherComprehensiveIncomeLossForeignCurrencyTransactionAndTranslationAdjustmentNetOfTax" xlink:label="us-gaap_OtherComprehensiveIncomeLossForeignCurrencyTransactionAndTranslationAdjustmentNetOfTax" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="20" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_OtherComprehensiveIncomeLossForeignCurrencyTransactionAndTranslationAdjustmentNetOfTax" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetIncomeLoss" xlink:label="us-gaap_NetIncomeLoss" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="21" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_NetIncomeLoss" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/StatementConsolidatedStatementsOfCashFlows" xlink:type="extended" xlink:title="00500 - Statement - Consolidated Statements of Cash Flows" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementTable" xlink:label="us-gaap_StatementTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsidiarySaleOfStockAxis" xlink:label="us-gaap_SubsidiarySaleOfStockAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_StatementTable" xlink:to="us-gaap_SubsidiarySaleOfStockAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_AtMarketIssuanceSalesAgreementMember" xlink:label="sngx_AtMarketIssuanceSalesAgreementMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sngx_AtMarketIssuanceSalesAgreementMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PublicOfferingMember" xlink:label="sngx_PublicOfferingMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sngx_PublicOfferingMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementLineItems" xlink:label="us-gaap_StatementLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_StatementTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ProfitLoss" xlink:label="us-gaap_ProfitLoss" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_ProfitLoss" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:label="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CostOfGoodsAndServicesSoldDepreciationAndAmortization" xlink:label="us-gaap_CostOfGoodsAndServicesSoldDepreciationAndAmortization" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_CostOfGoodsAndServicesSoldDepreciationAndAmortization" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense" xlink:label="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_OperatingLeaseRightOfUseAssetAmortizationExpense" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensation" xlink:label="us-gaap_ShareBasedCompensation" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_ShareBasedCompensation" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IssuanceOfStockAndWarrantsForServicesOrClaims" xlink:label="us-gaap_IssuanceOfStockAndWarrantsForServicesOrClaims" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_IssuanceOfStockAndWarrantsForServicesOrClaims" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_FairValueAdjustmentOfConvertibleDebt" xlink:label="sngx_FairValueAdjustmentOfConvertibleDebt" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_AdjustmentsToReconcileNetIncomeLossToCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="sngx_FairValueAdjustmentOfConvertibleDebt" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:label="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInAccountsAndOtherReceivables" xlink:label="us-gaap_IncreaseDecreaseInAccountsAndOtherReceivables" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInAccountsAndOtherReceivables" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInPrepaidExpense" xlink:label="us-gaap_IncreaseDecreaseInPrepaidExpense" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInPrepaidExpense" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInOtherReceivables" xlink:label="us-gaap_IncreaseDecreaseInOtherReceivables" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInOtherReceivables" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInOperatingLeaseLiability" xlink:label="us-gaap_IncreaseDecreaseInOperatingLeaseLiability" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInOperatingLeaseLiability" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInOtherAccountsPayableAndAccruedLiabilities" xlink:label="us-gaap_IncreaseDecreaseInOtherAccountsPayableAndAccruedLiabilities" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInOtherAccountsPayableAndAccruedLiabilities" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncreaseDecreaseInOtherEmployeeRelatedLiabilities" xlink:label="us-gaap_IncreaseDecreaseInOtherEmployeeRelatedLiabilities" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_IncreaseDecreaseInOperatingCapitalAbstract" xlink:to="us-gaap_IncreaseDecreaseInOtherEmployeeRelatedLiabilities" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivities" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_NetCashProvidedByUsedInOperatingActivitiesAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInOperatingActivities" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:label="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" xlink:label="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:to="us-gaap_PaymentsToAcquirePropertyPlantAndEquipment" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivities" xlink:label="us-gaap_NetCashProvidedByUsedInInvestingActivities" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_NetCashProvidedByUsedInInvestingActivitiesAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInInvestingActivities" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ProceedsFromIssuanceOfCommonStockPursuantToMarketSalesAgreement" xlink:label="sngx_ProceedsFromIssuanceOfCommonStockPursuantToMarketSalesAgreement" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="sngx_ProceedsFromIssuanceOfCommonStockPursuantToMarketSalesAgreement" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PaymentsOfStockIssuanceCosts" xlink:label="us-gaap_PaymentsOfStockIssuanceCosts" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_PaymentsOfStockIssuanceCosts" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ProceedsFromIssuanceOfCommonStockAndWarrants" xlink:label="sngx_ProceedsFromIssuanceOfCommonStockAndWarrants" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="sngx_ProceedsFromIssuanceOfCommonStockAndWarrants" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ProceedsFromWarrantExercises" xlink:label="us-gaap_ProceedsFromWarrantExercises" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_ProceedsFromWarrantExercises" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PaymentsOfWarrantIssuanceCostsUponInducement" xlink:label="sngx_PaymentsOfWarrantIssuanceCostsUponInducement" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="sngx_PaymentsOfWarrantIssuanceCostsUponInducement" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RepaymentsOfConvertibleDebt" xlink:label="us-gaap_RepaymentsOfConvertibleDebt" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_RepaymentsOfConvertibleDebt" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivities" xlink:label="us-gaap_NetCashProvidedByUsedInFinancingActivities" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="us-gaap_NetCashProvidedByUsedInFinancingActivitiesAbstract" xlink:to="us-gaap_NetCashProvidedByUsedInFinancingActivities" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_EffectOfExchangeRateOnCashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" xlink:label="us-gaap_EffectOfExchangeRateOnCashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_EffectOfExchangeRateOnCashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" xlink:label="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" xlink:label="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalents" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SupplementalCashFlowInformationAbstract" xlink:label="us-gaap_SupplementalCashFlowInformationAbstract" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="8" xlink:from="us-gaap_StatementLineItems" xlink:to="us-gaap_SupplementalCashFlowInformationAbstract" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxesPaid" xlink:label="us-gaap_IncomeTaxesPaid" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_SupplementalCashFlowInformationAbstract" xlink:to="us-gaap_IncomeTaxesPaid" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_InterestPaidNet" xlink:label="us-gaap_InterestPaidNet" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_SupplementalCashFlowInformationAbstract" xlink:to="us-gaap_InterestPaidNet" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AdditionalCashFlowElementsAbstract" xlink:label="us-gaap_AdditionalCashFlowElementsAbstract" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_SupplementalCashFlowInformationAbstract" xlink:to="us-gaap_AdditionalCashFlowElementsAbstract" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_OperatingLeasePaid" xlink:label="sngx_OperatingLeasePaid" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_AdditionalCashFlowElementsAbstract" xlink:to="sngx_OperatingLeasePaid" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NoncashInvestingAndFinancingItemsAbstract" xlink:label="us-gaap_NoncashInvestingAndFinancingItemsAbstract" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_SupplementalCashFlowInformationAbstract" xlink:to="us-gaap_NoncashInvestingAndFinancingItemsAbstract" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DebtConversionConvertedInstrumentAmount1" xlink:label="us-gaap_DebtConversionConvertedInstrumentAmount1" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_NoncashInvestingAndFinancingItemsAbstract" xlink:to="us-gaap_DebtConversionConvertedInstrumentAmount1" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RightOfUseAssetObtainedInExchangeForOperatingLeaseLiability" xlink:label="us-gaap_RightOfUseAssetObtainedInExchangeForOperatingLeaseLiability" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_NoncashInvestingAndFinancingItemsAbstract" xlink:to="us-gaap_RightOfUseAssetObtainedInExchangeForOperatingLeaseLiability" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_NoncashOrPartNoncashDeferredIssuanceCostReclassifiedToAdditionalPaidInCapital" xlink:label="sngx_NoncashOrPartNoncashDeferredIssuanceCostReclassifiedToAdditionalPaidInCapital" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_NoncashInvestingAndFinancingItemsAbstract" xlink:to="sngx_NoncashOrPartNoncashDeferredIssuanceCostReclassifiedToAdditionalPaidInCapital" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockIssuanceCostsIncludedInAccountsPayableAndAccruedExpenses" xlink:label="sngx_StockIssuanceCostsIncludedInAccountsPayableAndAccruedExpenses" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_NoncashInvestingAndFinancingItemsAbstract" xlink:to="sngx_StockIssuanceCostsIncludedInAccountsPayableAndAccruedExpenses" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_IssuanceCostOfWarrantExercise" xlink:label="sngx_IssuanceCostOfWarrantExercise" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_NoncashInvestingAndFinancingItemsAbstract" xlink:to="sngx_IssuanceCostOfWarrantExercise" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockTables" xlink:type="extended" xlink:title="30803 - Disclosure - Stock Option Plans and Warrants to Purchase Common Stock (Tables)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:label="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AwardTypeAxis" xlink:label="us-gaap_AwardTypeAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" xlink:to="us-gaap_AwardTypeAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_EquityIncentivePlan2025Member" xlink:label="sngx_EquityIncentivePlan2025Member" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="sngx_EquityIncentivePlan2025Member" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_EmployeeStockOptionMember" xlink:label="us-gaap_EmployeeStockOptionMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_EmployeeStockOptionMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockCompensationPlanMember" xlink:label="us-gaap_StockCompensationPlanMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_StockCompensationPlanMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_WarrantMember" xlink:label="us-gaap_WarrantMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_WarrantMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationArrangementsByShareBasedPaymentAwardTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfShareBasedCompensationActivityTableTextBlock" xlink:label="us-gaap_ScheduleOfShareBasedCompensationActivityTableTextBlock" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationActivityTableTextBlock" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfShareBasedCompensationStockOptionsActivityTableTextBlock" xlink:label="us-gaap_ScheduleOfShareBasedCompensationStockOptionsActivityTableTextBlock" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationStockOptionsActivityTableTextBlock" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_Sharebasedpaymentsarrangementoptionexercisepricerangetabletextblock" xlink:label="sngx_Sharebasedpaymentsarrangementoptionexercisepricerangetabletextblock" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="sngx_Sharebasedpaymentsarrangementoptionexercisepricerangetabletextblock" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfCompensationCostForShareBasedPaymentArrangementsAllocationOfShareBasedCompensationCostsByPlanTableTextBlock" xlink:label="us-gaap_ScheduleOfCompensationCostForShareBasedPaymentArrangementsAllocationOfShareBasedCompensationCostsByPlanTableTextBlock" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfCompensationCostForShareBasedPaymentArrangementsAllocationOfShareBasedCompensationCostsByPlanTableTextBlock" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfOtherShareBasedCompensationActivityTableTextBlock" xlink:label="us-gaap_ScheduleOfOtherShareBasedCompensationActivityTableTextBlock" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfOtherShareBasedCompensationActivityTableTextBlock" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTextBlock" xlink:label="us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTextBlock" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTextBlock" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureNatureOfBusinessDetails" xlink:type="extended" xlink:title="40101 - Disclosure - Nature of Business (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" xlink:label="us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ProductOrServiceAxis" xlink:label="srt_ProductOrServiceAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" xlink:to="srt_ProductOrServiceAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ProductsAndServicesDomain" xlink:label="srt_ProductsAndServicesDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_ProductOrServiceAxis" xlink:to="srt_ProductsAndServicesDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_HybryteMember" xlink:label="sngx_HybryteMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_ProductsAndServicesDomain" xlink:to="sngx_HybryteMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventTypeAxis" xlink:label="us-gaap_SubsequentEventTypeAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="2" xlink:from="us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" xlink:to="us-gaap_SubsequentEventTypeAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventTypeDomain" xlink:label="us-gaap_SubsequentEventTypeDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_SubsequentEventTypeAxis" xlink:to="us-gaap_SubsequentEventTypeDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventMember" xlink:label="us-gaap_SubsequentEventMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_SubsequentEventTypeDomain" xlink:to="us-gaap_SubsequentEventMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsidiarySaleOfStockAxis" xlink:label="us-gaap_SubsidiarySaleOfStockAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="3" xlink:from="us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" xlink:to="us-gaap_SubsidiarySaleOfStockAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_AtMarketIssuanceSalesMember" xlink:label="sngx_AtMarketIssuanceSalesMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sngx_AtMarketIssuanceSalesMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:label="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="us-gaap_ScheduleOfCollaborativeArrangementsAndNoncollaborativeArrangementTransactionsTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NumberOfOperatingSegments" xlink:label="us-gaap_NumberOfOperatingSegments" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="us-gaap_NumberOfOperatingSegments" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CollaborativeArrangementTransactionStatementOfIncomeOrComprehensiveIncomeExtensibleEnumeration" xlink:label="us-gaap_CollaborativeArrangementTransactionStatementOfIncomeOrComprehensiveIncomeExtensibleEnumeration" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="us-gaap_CollaborativeArrangementTransactionStatementOfIncomeOrComprehensiveIncomeExtensibleEnumeration" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RevenueFromCollaborativeArrangementExcludingRevenueFromContractWithCustomer" xlink:label="us-gaap_RevenueFromCollaborativeArrangementExcludingRevenueFromContractWithCustomer" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="us-gaap_RevenueFromCollaborativeArrangementExcludingRevenueFromContractWithCustomer" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_GuaranteeObligationsTermDuration" xlink:label="sngx_GuaranteeObligationsTermDuration" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sngx_GuaranteeObligationsTermDuration" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RetainedEarningsAccumulatedDeficit" xlink:label="us-gaap_RetainedEarningsAccumulatedDeficit" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="us-gaap_RetainedEarningsAccumulatedDeficit" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_WorkingCapitalCarryingValue" xlink:label="sngx_WorkingCapitalCarryingValue" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sngx_WorkingCapitalCarryingValue" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetIncomeLoss" xlink:label="us-gaap_NetIncomeLoss" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="8" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="us-gaap_NetIncomeLoss" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivities" xlink:label="us-gaap_NetCashProvidedByUsedInOperatingActivities" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="9" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="us-gaap_NetCashProvidedByUsedInOperatingActivities" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_SaleOfStockAggregateValueOfSharesToBeIssuedInTransaction" xlink:label="sngx_SaleOfStockAggregateValueOfSharesToBeIssuedInTransaction" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="10" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sngx_SaleOfStockAggregateValueOfSharesToBeIssuedInTransaction" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_CommonStockValueOfSharesReservedForFutureIssuance" xlink:label="sngx_CommonStockValueOfSharesReservedForFutureIssuance" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="11" xlink:from="us-gaap_CollaborativeArrangementsAndNoncollaborativeArrangementTransactionsLineItems" xlink:to="sngx_CommonStockValueOfSharesReservedForFutureIssuance" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureSummaryOfSignificantAccountingPoliciesDetails" xlink:type="extended" xlink:title="40201 - Disclosure - Summary of Significant Accounting Policies (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable" xlink:label="us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_TitleOfIndividualAxis" xlink:label="srt_TitleOfIndividualAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable" xlink:to="srt_TitleOfIndividualAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_TitleOfIndividualWithRelationshipToEntityDomain" xlink:label="srt_TitleOfIndividualWithRelationshipToEntityDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_TitleOfIndividualAxis" xlink:to="srt_TitleOfIndividualWithRelationshipToEntityDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_DirectorMember" xlink:label="srt_DirectorMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_TitleOfIndividualWithRelationshipToEntityDomain" xlink:to="srt_DirectorMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RestructuringCostAndReserveAxis" xlink:label="us-gaap_RestructuringCostAndReserveAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="2" xlink:from="us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable" xlink:to="us-gaap_RestructuringCostAndReserveAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_TypeOfRestructuringDomain" xlink:label="us-gaap_TypeOfRestructuringDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_RestructuringCostAndReserveAxis" xlink:to="us-gaap_TypeOfRestructuringDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OneTimeTerminationBenefitsMember" xlink:label="us-gaap_OneTimeTerminationBenefitsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_TypeOfRestructuringDomain" xlink:to="us-gaap_OneTimeTerminationBenefitsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:label="us-gaap_FiniteLivedIntangibleAssetsLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_ScheduleOfFiniteLivedIntangibleAssetsTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NumberOfOperatingSegments" xlink:label="us-gaap_NumberOfOperatingSegments" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_NumberOfOperatingSegments" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ImpairmentOfIntangibleAssetsFinitelived" xlink:label="us-gaap_ImpairmentOfIntangibleAssetsFinitelived" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_ImpairmentOfIntangibleAssetsFinitelived" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ShareBasedCompensationArrangementServicePeriod" xlink:label="sngx_ShareBasedCompensationArrangementServicePeriod" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="sngx_ShareBasedCompensationArrangementServicePeriod" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingRights" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingRights" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardAwardVestingRights" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_SharebasedCompensationExpirationPeriod" xlink:label="sngx_SharebasedCompensationExpirationPeriod" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="sngx_SharebasedCompensationExpirationPeriod" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedDividendRate" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="8" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardFairValueAssumptionsExpectedTerm1" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedVolatilityRateMinimum" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedVolatilityRateMinimum" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="9" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedVolatilityRateMinimum" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedVolatilityRateMaximum" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedVolatilityRateMaximum" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="10" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsExpectedVolatilityRateMaximum" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRateMinimum" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRateMinimum" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="11" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRateMinimum" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRateMaximum" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRateMaximum" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="12" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardFairValueAssumptionsRiskFreeInterestRateMaximum" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeTaxExpenseBenefit" xlink:label="us-gaap_IncomeTaxExpenseBenefit" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="13" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_IncomeTaxExpenseBenefit" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_UnrecognizedTaxBenefitsInterestOnIncomeTaxesAccrued" xlink:label="us-gaap_UnrecognizedTaxBenefitsInterestOnIncomeTaxesAccrued" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="14" xlink:from="us-gaap_FiniteLivedIntangibleAssetsLineItems" xlink:to="us-gaap_UnrecognizedTaxBenefitsInterestOnIncomeTaxesAccrued" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureSummaryOfSignificantAccountingPoliciesLossPerShareDetails" xlink:type="extended" xlink:title="40202 - Disclosure - Summary of Significant Accounting Policies - Loss per share (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable" xlink:label="us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:label="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable" xlink:to="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AntidilutiveSecuritiesNameDomain" xlink:label="us-gaap_AntidilutiveSecuritiesNameDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareByAntidilutiveSecuritiesAxis" xlink:to="us-gaap_AntidilutiveSecuritiesNameDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_WarrantMember" xlink:label="us-gaap_WarrantMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_AntidilutiveSecuritiesNameDomain" xlink:to="us-gaap_WarrantMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_EmployeeStockOptionMember" xlink:label="us-gaap_EmployeeStockOptionMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_AntidilutiveSecuritiesNameDomain" xlink:to="us-gaap_EmployeeStockOptionMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ConvertibleDebtSecuritiesMember" xlink:label="us-gaap_ConvertibleDebtSecuritiesMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_AntidilutiveSecuritiesNameDomain" xlink:to="us-gaap_ConvertibleDebtSecuritiesMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems" xlink:label="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems" xlink:to="us-gaap_ScheduleOfAntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount" xlink:label="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareLineItems" xlink:to="us-gaap_AntidilutiveSecuritiesExcludedFromComputationOfEarningsPerShareAmount" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureLeasesDetails" xlink:type="extended" xlink:title="40301 - Disclosure - Leases (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LesseeLeaseDescriptionTable" xlink:label="us-gaap_LesseeLeaseDescriptionTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_StatementScenarioAxis" xlink:label="srt_StatementScenarioAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_LesseeLeaseDescriptionTable" xlink:to="srt_StatementScenarioAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ScenarioUnspecifiedDomain" xlink:label="srt_ScenarioUnspecifiedDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_StatementScenarioAxis" xlink:to="srt_ScenarioUnspecifiedDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_LeasePaymentsApplicableFromNovember2026ToOctober2027Member" xlink:label="sngx_LeasePaymentsApplicableFromNovember2026ToOctober2027Member" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_ScenarioUnspecifiedDomain" xlink:to="sngx_LeasePaymentsApplicableFromNovember2026ToOctober2027Member" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_LeasePaymentsApplicableFromNovember2027UntilExpirationMember" xlink:label="sngx_LeasePaymentsApplicableFromNovember2027UntilExpirationMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="srt_ScenarioUnspecifiedDomain" xlink:to="sngx_LeasePaymentsApplicableFromNovember2027UntilExpirationMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LesseeLeaseDescriptionLineItems" xlink:label="us-gaap_LesseeLeaseDescriptionLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="us-gaap_LesseeLeaseDescriptionTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_LeaseRentalPerMonth" xlink:label="sngx_LeaseRentalPerMonth" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_LesseeLeaseDescriptionLineItems" xlink:to="sngx_LeaseRentalPerMonth" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureDebtDetails" xlink:type="extended" xlink:title="40501 - Disclosure - Debt (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DebtInstrumentTable" xlink:label="us-gaap_DebtInstrumentTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongtermDebtTypeAxis" xlink:label="us-gaap_LongtermDebtTypeAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="us-gaap_LongtermDebtTypeAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongtermDebtTypeDomain" xlink:label="us-gaap_LongtermDebtTypeDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_LongtermDebtTypeAxis" xlink:to="us-gaap_LongtermDebtTypeDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ConvertibleDebtMember" xlink:label="us-gaap_ConvertibleDebtMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_LongtermDebtTypeDomain" xlink:to="us-gaap_ConvertibleDebtMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_CounterpartyNameAxis" xlink:label="srt_CounterpartyNameAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="2" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="srt_CounterpartyNameAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_RepurchaseAgreementCounterpartyNameDomain" xlink:label="srt_RepurchaseAgreementCounterpartyNameDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_CounterpartyNameAxis" xlink:to="srt_RepurchaseAgreementCounterpartyNameDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PontifaxMedisonFinanceMember" xlink:label="sngx_PontifaxMedisonFinanceMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_RepurchaseAgreementCounterpartyNameDomain" xlink:to="sngx_PontifaxMedisonFinanceMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_StatementScenarioAxis" xlink:label="srt_StatementScenarioAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="3" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="srt_StatementScenarioAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ScenarioUnspecifiedDomain" xlink:label="srt_ScenarioUnspecifiedDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_StatementScenarioAxis" xlink:to="srt_ScenarioUnspecifiedDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_NumberOfFirstEquityInstrumentsCommonStockIssuableUponConversionMember" xlink:label="sngx_NumberOfFirstEquityInstrumentsCommonStockIssuableUponConversionMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_ScenarioUnspecifiedDomain" xlink:to="sngx_NumberOfFirstEquityInstrumentsCommonStockIssuableUponConversionMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_LoanAgreementAmendment2024ConversionPriceTrancheOneMember" xlink:label="sngx_LoanAgreementAmendment2024ConversionPriceTrancheOneMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="srt_ScenarioUnspecifiedDomain" xlink:to="sngx_LoanAgreementAmendment2024ConversionPriceTrancheOneMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_LoanAgreementAmendment2024ConversionPriceTrancheTwoMember" xlink:label="sngx_LoanAgreementAmendment2024ConversionPriceTrancheTwoMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="srt_ScenarioUnspecifiedDomain" xlink:to="sngx_LoanAgreementAmendment2024ConversionPriceTrancheTwoMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DebtInstrumentAxis" xlink:label="us-gaap_DebtInstrumentAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="4" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="us-gaap_DebtInstrumentAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DebtInstrumentNameDomain" xlink:label="us-gaap_DebtInstrumentNameDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_DebtInstrumentAxis" xlink:to="us-gaap_DebtInstrumentNameDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_FirstTrancheMember" xlink:label="sngx_FirstTrancheMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_DebtInstrumentNameDomain" xlink:to="sngx_FirstTrancheMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_RangeAxis" xlink:label="srt_RangeAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="5" xlink:from="us-gaap_DebtInstrumentTable" xlink:to="srt_RangeAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_RangeMember" xlink:label="srt_RangeMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_RangeAxis" xlink:to="srt_RangeMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_MaximumMember" xlink:label="srt_MaximumMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_RangeMember" xlink:to="srt_MaximumMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DebtInstrumentLineItems" xlink:label="us-gaap_DebtInstrumentLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DebtInstrumentFaceAmount" xlink:label="us-gaap_DebtInstrumentFaceAmount" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentFaceAmount" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DebtInstrumentInterestRateStatedPercentage" xlink:label="us-gaap_DebtInstrumentInterestRateStatedPercentage" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentInterestRateStatedPercentage" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LineOfCreditFacilityCommitmentFeePercentage" xlink:label="us-gaap_LineOfCreditFacilityCommitmentFeePercentage" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_LineOfCreditFacilityCommitmentFeePercentage" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_DebtInstrumentPeriodPrincipalPaymentDeferred" xlink:label="sngx_DebtInstrumentPeriodPrincipalPaymentDeferred" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sngx_DebtInstrumentPeriodPrincipalPaymentDeferred" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ConvertibleNotesPayable" xlink:label="us-gaap_ConvertibleNotesPayable" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_ConvertibleNotesPayable" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RepaymentsOfDebt" xlink:label="us-gaap_RepaymentsOfDebt" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_RepaymentsOfDebt" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongTermDebt" xlink:label="us-gaap_LongTermDebt" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="8" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_LongTermDebt" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_DebtInstrumentReductionInConversionPricePercentageOfClosingPriceClosingPriceOfCommonStockOnDayBeforeDeliveryOfConversionNotice" xlink:label="sngx_DebtInstrumentReductionInConversionPricePercentageOfClosingPriceClosingPriceOfCommonStockOnDayBeforeDeliveryOfConversionNotice" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="9" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sngx_DebtInstrumentReductionInConversionPricePercentageOfClosingPriceClosingPriceOfCommonStockOnDayBeforeDeliveryOfConversionNotice" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities" xlink:label="us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="10" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_DebtInstrumentReductionInConversionPriceNotice" xlink:label="sngx_DebtInstrumentReductionInConversionPriceNotice" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="11" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sngx_DebtInstrumentReductionInConversionPriceNotice" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_FairValueAdjustmentOfConvertibleDebt" xlink:label="sngx_FairValueAdjustmentOfConvertibleDebt" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="12" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sngx_FairValueAdjustmentOfConvertibleDebt" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_RepaymentsOfConvertibleDebt" xlink:label="us-gaap_RepaymentsOfConvertibleDebt" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="13" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_RepaymentsOfConvertibleDebt" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DebtInstrumentConvertibleConversionPrice1" xlink:label="us-gaap_DebtInstrumentConvertibleConversionPrice1" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="14" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="us-gaap_DebtInstrumentConvertibleConversionPrice1" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_DebtInstrumentConvertibleNumberOfSharesToBeIssued" xlink:label="sngx_DebtInstrumentConvertibleNumberOfSharesToBeIssued" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="15" xlink:from="us-gaap_DebtInstrumentLineItems" xlink:to="sngx_DebtInstrumentConvertibleNumberOfSharesToBeIssued" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureShareholdersEquityDetails" xlink:type="extended" xlink:title="40701 - Disclosure - Shareholders' Equity (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfStockByClassTable" xlink:label="us-gaap_ScheduleOfStockByClassTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementEquityComponentsAxis" xlink:label="us-gaap_StatementEquityComponentsAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="us-gaap_StatementEquityComponentsAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_EquityComponentDomain" xlink:label="us-gaap_EquityComponentDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CommonStockMember" xlink:label="us-gaap_CommonStockMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_CommonStockMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongtermDebtTypeAxis" xlink:label="us-gaap_LongtermDebtTypeAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="2" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="us-gaap_LongtermDebtTypeAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongtermDebtTypeDomain" xlink:label="us-gaap_LongtermDebtTypeDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_LongtermDebtTypeAxis" xlink:to="us-gaap_LongtermDebtTypeDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ConvertibleDebtMember" xlink:label="us-gaap_ConvertibleDebtMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_LongtermDebtTypeDomain" xlink:to="us-gaap_ConvertibleDebtMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_CounterpartyNameAxis" xlink:label="srt_CounterpartyNameAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="3" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="srt_CounterpartyNameAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_RepurchaseAgreementCounterpartyNameDomain" xlink:label="srt_RepurchaseAgreementCounterpartyNameDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_CounterpartyNameAxis" xlink:to="srt_RepurchaseAgreementCounterpartyNameDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PontifaxMedisonFinanceMember" xlink:label="sngx_PontifaxMedisonFinanceMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_RepurchaseAgreementCounterpartyNameDomain" xlink:to="sngx_PontifaxMedisonFinanceMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsidiarySaleOfStockAxis" xlink:label="us-gaap_SubsidiarySaleOfStockAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="4" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="us-gaap_SubsidiarySaleOfStockAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PublicOfferingMember" xlink:label="sngx_PublicOfferingMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sngx_PublicOfferingMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_AtMarketIssuanceSalesMember" xlink:label="sngx_AtMarketIssuanceSalesMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sngx_AtMarketIssuanceSalesMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ClassOfWarrantOrRightAxis" xlink:label="us-gaap_ClassOfWarrantOrRightAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="5" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="us-gaap_ClassOfWarrantOrRightAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ClassOfWarrantOrRightDomain" xlink:label="us-gaap_ClassOfWarrantOrRightDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_ClassOfWarrantOrRightAxis" xlink:to="us-gaap_ClassOfWarrantOrRightDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PreFundedWarrantsMember" xlink:label="sngx_PreFundedWarrantsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_ClassOfWarrantOrRightDomain" xlink:to="sngx_PreFundedWarrantsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_NewWarrantsMember" xlink:label="sngx_NewWarrantsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_ClassOfWarrantOrRightDomain" xlink:to="sngx_NewWarrantsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ExistingWarrantsMember" xlink:label="sngx_ExistingWarrantsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_ClassOfWarrantOrRightDomain" xlink:to="sngx_ExistingWarrantsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_WarrantModificationAndNewWarrantsMember" xlink:label="sngx_WarrantModificationAndNewWarrantsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_ClassOfWarrantOrRightDomain" xlink:to="sngx_WarrantModificationAndNewWarrantsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_MeasurementInputTypeAxis" xlink:label="us-gaap_MeasurementInputTypeAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="6" xlink:from="us-gaap_ScheduleOfStockByClassTable" xlink:to="us-gaap_MeasurementInputTypeAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_MeasurementInputTypeDomain" xlink:label="us-gaap_MeasurementInputTypeDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_MeasurementInputTypeAxis" xlink:to="us-gaap_MeasurementInputTypeDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_MeasurementInputExpectedDividendRateMember" xlink:label="us-gaap_MeasurementInputExpectedDividendRateMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_MeasurementInputTypeDomain" xlink:to="us-gaap_MeasurementInputExpectedDividendRateMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_MeasurementInputExpectedTermMember" xlink:label="us-gaap_MeasurementInputExpectedTermMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_MeasurementInputTypeDomain" xlink:to="us-gaap_MeasurementInputExpectedTermMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_MeasurementInputPriceVolatilityMember" xlink:label="us-gaap_MeasurementInputPriceVolatilityMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_MeasurementInputTypeDomain" xlink:to="us-gaap_MeasurementInputPriceVolatilityMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_MeasurementInputRiskFreeInterestRateMember" xlink:label="us-gaap_MeasurementInputRiskFreeInterestRateMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_MeasurementInputTypeDomain" xlink:to="us-gaap_MeasurementInputRiskFreeInterestRateMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ClassOfStockLineItems" xlink:label="us-gaap_ClassOfStockLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_ScheduleOfStockByClassTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodSharesNewIssues" xlink:label="us-gaap_StockIssuedDuringPeriodSharesNewIssues" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesNewIssues" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ClassOfWarrantOrRightNumberOfSecuritiesCalledByWarrantsOrRights" xlink:label="us-gaap_ClassOfWarrantOrRightNumberOfSecuritiesCalledByWarrantsOrRights" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_ClassOfWarrantOrRightNumberOfSecuritiesCalledByWarrantsOrRights" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SharePrice" xlink:label="us-gaap_SharePrice" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_SharePrice" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ClassOfWarrantOrRightExercisePriceOfWarrantsOrRights1" xlink:label="us-gaap_ClassOfWarrantOrRightExercisePriceOfWarrantsOrRights1" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_ClassOfWarrantOrRightExercisePriceOfWarrantsOrRights1" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_WarrantsAndRightsOutstanding" xlink:label="us-gaap_WarrantsAndRightsOutstanding" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_WarrantsAndRightsOutstanding" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodSharesIssuedForServices" xlink:label="us-gaap_StockIssuedDuringPeriodSharesIssuedForServices" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesIssuedForServices" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_WeightedAverageSharePrice" xlink:label="sngx_WeightedAverageSharePrice" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="8" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sngx_WeightedAverageSharePrice" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockIssuedDuringPeriodShareExerciseOfWarrants" xlink:label="sngx_StockIssuedDuringPeriodShareExerciseOfWarrants" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="9" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sngx_StockIssuedDuringPeriodShareExerciseOfWarrants" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_SaleOfStockCompensationPercentageOnGrossProceeds" xlink:label="sngx_SaleOfStockCompensationPercentageOnGrossProceeds" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="10" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sngx_SaleOfStockCompensationPercentageOnGrossProceeds" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_SaleOfStockAggregateValueOfSharesToBeIssuedInTransaction" xlink:label="sngx_SaleOfStockAggregateValueOfSharesToBeIssuedInTransaction" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="11" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sngx_SaleOfStockAggregateValueOfSharesToBeIssuedInTransaction" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities" xlink:label="us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="12" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesConversionOfConvertibleSecurities" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DebtInstrumentConvertibleConversionPrice1" xlink:label="us-gaap_DebtInstrumentConvertibleConversionPrice1" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="13" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_DebtInstrumentConvertibleConversionPrice1" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_DebtInstrumentReductionInConversionPricePercentageOfClosingPriceClosingPriceOfCommonStockOnDayBeforeDeliveryOfConversionNotice" xlink:label="sngx_DebtInstrumentReductionInConversionPricePercentageOfClosingPriceClosingPriceOfCommonStockOnDayBeforeDeliveryOfConversionNotice" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="14" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sngx_DebtInstrumentReductionInConversionPricePercentageOfClosingPriceClosingPriceOfCommonStockOnDayBeforeDeliveryOfConversionNotice" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ClassOfWarrantOrRightPercentageOfExistingWarrantSharesToNewWarrantShareIssues" xlink:label="sngx_ClassOfWarrantOrRightPercentageOfExistingWarrantSharesToNewWarrantShareIssues" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="15" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sngx_ClassOfWarrantOrRightPercentageOfExistingWarrantSharesToNewWarrantShareIssues" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ProceedsFromWarrantExercises" xlink:label="us-gaap_ProceedsFromWarrantExercises" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="16" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_ProceedsFromWarrantExercises" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PaymentsOfWarrantIssuanceCostsUponInducement" xlink:label="sngx_PaymentsOfWarrantIssuanceCostsUponInducement" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="17" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sngx_PaymentsOfWarrantIssuanceCostsUponInducement" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_WarrantIssuanceCostsFinancialAndLegalFees" xlink:label="sngx_WarrantIssuanceCostsFinancialAndLegalFees" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="18" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sngx_WarrantIssuanceCostsFinancialAndLegalFees" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_IssuanceCostOfWarrantExercise" xlink:label="sngx_IssuanceCostOfWarrantExercise" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="19" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sngx_IssuanceCostOfWarrantExercise" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_WarrantsAndRightsIssuedShares" xlink:label="sngx_WarrantsAndRightsIssuedShares" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="20" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="sngx_WarrantsAndRightsIssuedShares" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_WarrantsAndRightsOutstandingMeasurementInput" xlink:label="us-gaap_WarrantsAndRightsOutstandingMeasurementInput" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="21" xlink:from="us-gaap_ClassOfStockLineItems" xlink:to="us-gaap_WarrantsAndRightsOutstandingMeasurementInput" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockDetails" xlink:type="extended" xlink:title="40801 - Disclosure - Stock Option Plans and Warrants to Purchase Common Stock (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsTable" xlink:label="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PlanNameAxis" xlink:label="us-gaap_PlanNameAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsTable" xlink:to="us-gaap_PlanNameAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PlanNameDomain" xlink:label="us-gaap_PlanNameDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_PlanNameAxis" xlink:to="us-gaap_PlanNameDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_Grant2015PlanMember" xlink:label="sngx_Grant2015PlanMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_PlanNameDomain" xlink:to="sngx_Grant2015PlanMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_EquityIncentivePlan2025Member" xlink:label="sngx_EquityIncentivePlan2025Member" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_PlanNameDomain" xlink:to="sngx_EquityIncentivePlan2025Member" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_EquityIncentivePlan2005Member" xlink:label="sngx_EquityIncentivePlan2005Member" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_PlanNameDomain" xlink:to="sngx_EquityIncentivePlan2005Member" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AwardTypeAxis" xlink:label="us-gaap_AwardTypeAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="2" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsTable" xlink:to="us-gaap_AwardTypeAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_EmployeeStockOptionMember" xlink:label="us-gaap_EmployeeStockOptionMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_EmployeeStockOptionMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsLineItems" xlink:label="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsLineItems" xlink:to="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" xlink:label="us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsLineItems" xlink:to="us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfEquityPrograms" xlink:label="sngx_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfEquityPrograms" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsLineItems" xlink:to="sngx_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfEquityPrograms" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsOutstandingNumber" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardCompensationCost1" xlink:label="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardCompensationCost1" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsLineItems" xlink:to="us-gaap_SharebasedCompensationArrangementBySharebasedPaymentAwardCompensationCost1" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" xlink:label="us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="8" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsLineItems" xlink:to="us-gaap_EmployeeServiceShareBasedCompensationNonvestedAwardsTotalCompensationCostNotYetRecognizedPeriodForRecognition1" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfSharesAvailableForGrantUnder2025PlanDetails" xlink:type="extended" xlink:title="40802 - Disclosure - Stock Option Plans and Warrants to Purchase Common Stock - Schedule of shares available for grant under the 2025 plan (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanTable" xlink:label="sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PlanNameAxis" xlink:label="us-gaap_PlanNameAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanTable" xlink:to="us-gaap_PlanNameAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_PlanNameDomain" xlink:label="us-gaap_PlanNameDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_PlanNameAxis" xlink:to="us-gaap_PlanNameDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_EquityIncentivePlan2025Member" xlink:label="sngx_EquityIncentivePlan2025Member" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_PlanNameDomain" xlink:to="sngx_EquityIncentivePlan2025Member" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventTypeAxis" xlink:label="us-gaap_SubsequentEventTypeAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="2" xlink:from="sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanTable" xlink:to="us-gaap_SubsequentEventTypeAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventTypeDomain" xlink:label="us-gaap_SubsequentEventTypeDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_SubsequentEventTypeAxis" xlink:to="us-gaap_SubsequentEventTypeDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventMember" xlink:label="us-gaap_SubsequentEventMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_SubsequentEventTypeDomain" xlink:to="us-gaap_SubsequentEventMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanLineItems" xlink:label="sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanLineItems" xlink:to="sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAvailableForGrant" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriod" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriod" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardEquityInstrumentsOtherThanOptionsGrantsInPeriod" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_CommonStockCapitalSharesReservedForFutureIssuanceAdditions" xlink:label="sngx_CommonStockCapitalSharesReservedForFutureIssuanceAdditions" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanLineItems" xlink:to="sngx_CommonStockCapitalSharesReservedForFutureIssuanceAdditions" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" xlink:label="us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="sngx_StockOptionPlansAndWarrantsToPurchaseCommonStockDetailsScheduleOfSharesAvailableForGrantUnder2025PlanLineItems" xlink:to="us-gaap_CommonStockCapitalSharesReservedForFutureIssuance" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfWeightedAverageExercisePriceByPriceRangeForOutstandingOptionsToPurchaseCommonStockDetails" xlink:type="extended" xlink:title="40804 - Disclosure - Stock Option Plans and Warrants to Purchase Common Stock - Schedule of weighted-average exercise price, by price range, for outstanding options to purchase common stock (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockTable" xlink:label="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AwardTypeAxis" xlink:label="us-gaap_AwardTypeAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockTable" xlink:to="us-gaap_AwardTypeAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_EmployeeStockOptionMember" xlink:label="us-gaap_EmployeeStockOptionMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="us-gaap_EmployeeStockOptionMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="2" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockTable" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeAxis" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ExercisePriceRange1.37To10.78Member" xlink:label="sngx_ExercisePriceRange1.37To10.78Member" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="sngx_ExercisePriceRange1.37To10.78Member" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ExercisePriceRange129.60To640.80Member" xlink:label="sngx_ExercisePriceRange129.60To640.80Member" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="sngx_ExercisePriceRange129.60To640.80Member" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ExercisePriceRange1776Member" xlink:label="sngx_ExercisePriceRange1776Member" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeDomain" xlink:to="sngx_ExercisePriceRange1776Member" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockLineItems" xlink:label="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockLineItems" xlink:to="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLowerRangeLimit" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLowerRangeLimit" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockLineItems" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLowerRangeLimit" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeUpperRangeLimit" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeUpperRangeLimit" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockLineItems" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeUpperRangeLimit" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeOutstandingOptionsWeightedAveragesRemainingContractualTerm2" xlink:label="sngx_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeOutstandingOptionsWeightedAveragesRemainingContractualTerm2" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockLineItems" xlink:to="sngx_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeOutstandingOptionsWeightedAveragesRemainingContractualTerm2" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeNumberOfOutstandingOption" xlink:label="sngx_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeNumberOfOutstandingOption" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockLineItems" xlink:to="sngx_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeNumberOfOutstandingOption" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ShareBasedCompensationShareAuthorizedUnderStockOptionPlanExercisePriceRangeNumberOfExercisableOptions" xlink:label="sngx_ShareBasedCompensationShareAuthorizedUnderStockOptionPlanExercisePriceRangeNumberOfExercisableOptions" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofweightedaverageexercisepricebypricerangeforoutstandingoptionstopurchasecommonstockLineItems" xlink:to="sngx_ShareBasedCompensationShareAuthorizedUnderStockOptionPlanExercisePriceRangeNumberOfExercisableOptions" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfShareBasedCompensationExpenseDetails" xlink:type="extended" xlink:title="40805 - Disclosure - Stock Option Plans and Warrants to Purchase Common Stock - Schedule of share-based compensation expense (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofsharebasedcompensationexpenseTable" xlink:label="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofsharebasedcompensationexpenseTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeStatementLocationAxis" xlink:label="us-gaap_IncomeStatementLocationAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofsharebasedcompensationexpenseTable" xlink:to="us-gaap_IncomeStatementLocationAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeStatementLocationDomain" xlink:label="us-gaap_IncomeStatementLocationDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_IncomeStatementLocationAxis" xlink:to="us-gaap_IncomeStatementLocationDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ResearchAndDevelopmentExpenseMember" xlink:label="us-gaap_ResearchAndDevelopmentExpenseMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_IncomeStatementLocationDomain" xlink:to="us-gaap_ResearchAndDevelopmentExpenseMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_GeneralAndAdministrativeExpenseMember" xlink:label="us-gaap_GeneralAndAdministrativeExpenseMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_IncomeStatementLocationDomain" xlink:to="us-gaap_GeneralAndAdministrativeExpenseMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofsharebasedcompensationexpenseLineItems" xlink:label="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofsharebasedcompensationexpenseLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofsharebasedcompensationexpenseLineItems" xlink:to="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofsharebasedcompensationexpenseTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensation" xlink:label="us-gaap_ShareBasedCompensation" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofsharebasedcompensationexpenseLineItems" xlink:to="us-gaap_ShareBasedCompensation" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfWarrantActivityDetails" xlink:type="extended" xlink:title="40806 - Disclosure - Stock Option Plans and Warrants to Purchase Common Stock - Schedule of warrant activity (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityTable" xlink:label="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementEquityComponentsAxis" xlink:label="us-gaap_StatementEquityComponentsAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityTable" xlink:to="us-gaap_StatementEquityComponentsAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_EquityComponentDomain" xlink:label="us-gaap_EquityComponentDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_StatementEquityComponentsAxis" xlink:to="us-gaap_EquityComponentDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_WarrantMember" xlink:label="us-gaap_WarrantMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_EquityComponentDomain" xlink:to="us-gaap_WarrantMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityLineItems" xlink:label="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityLineItems" xlink:to="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ClassOfWarrantOrRightNumberOfSecuritiesCalledByWarrantsOrRights" xlink:label="us-gaap_ClassOfWarrantOrRightNumberOfSecuritiesCalledByWarrantsOrRights" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityLineItems" xlink:to="us-gaap_ClassOfWarrantOrRightNumberOfSecuritiesCalledByWarrantsOrRights" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ShareBasedCompensationArrangementByShareBasedPaymentWarrantOutstandingWeightedAverageExercisePrice" xlink:label="sngx_ShareBasedCompensationArrangementByShareBasedPaymentWarrantOutstandingWeightedAverageExercisePrice" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityLineItems" xlink:to="sngx_ShareBasedCompensationArrangementByShareBasedPaymentWarrantOutstandingWeightedAverageExercisePrice" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardOptionsGrantsInPeriodGross" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsGrantsInPeriodWeightedAverageExercisePrice" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" xlink:label="us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesStockOptionsExercised" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="sngx_StockOptionPlansandWarrantstoPurchaseCommonStockDetailsScheduleofwarrantactivityLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardOptionsExercisesInPeriodWeightedAverageExercisePrice" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureStockOptionPlansAndWarrantsToPurchaseCommonStockScheduleOfRemainingLifeByGrantDateForOutstandingWarrantsDetails" xlink:type="extended" xlink:title="40807 - Disclosure - Stock Option Plans and Warrants to Purchase Common Stock - Schedule of remaining life, by grant date, for outstanding warrants (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTable" xlink:label="us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_AwardTypeAxis" xlink:label="us-gaap_AwardTypeAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTable" xlink:to="us-gaap_AwardTypeAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:label="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_AwardTypeAxis" xlink:to="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_GrantDateOneMember" xlink:label="sngx_GrantDateOneMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="sngx_GrantDateOneMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_GrantDateTwoMember" xlink:label="sngx_GrantDateTwoMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="sngx_GrantDateTwoMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_GrantDateThreeMember" xlink:label="sngx_GrantDateThreeMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="sngx_GrantDateThreeMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_GrantDateFourMember" xlink:label="sngx_GrantDateFourMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_ShareBasedCompensationArrangementsByShareBasedPaymentAwardAwardTypeAndPlanNameDomain" xlink:to="sngx_GrantDateFourMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" xlink:to="us-gaap_ScheduleOfShareBasedCompensationSharesAuthorizedUnderStockOptionPlansByExercisePriceRangeTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeUpperRangeLimit" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeUpperRangeLimit" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeUpperRangeLimit" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeOutstandingOptionsWeightedAverageRemainingContractualTerm2" xlink:label="us-gaap_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeOutstandingOptionsWeightedAverageRemainingContractualTerm2" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" xlink:to="us-gaap_SharebasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeOutstandingOptionsWeightedAverageRemainingContractualTerm2" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeNumberOfOutstandingOptions" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeNumberOfOutstandingOptions" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeNumberOfOutstandingOptions" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeNumberOfExercisableOptions" xlink:label="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeNumberOfExercisableOptions" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeLineItems" xlink:to="us-gaap_ShareBasedCompensationSharesAuthorizedUnderStockOptionPlansExercisePriceRangeNumberOfExercisableOptions" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureCommitmentsAndContingenciesDetails" xlink:type="extended" xlink:title="41001 - Disclosure - Commitments and Contingencies (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OtherCommitmentsTable" xlink:label="us-gaap_OtherCommitmentsTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_GranteeStatusAxis" xlink:label="us-gaap_GranteeStatusAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_OtherCommitmentsTable" xlink:to="us-gaap_GranteeStatusAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_GranteeStatusDomain" xlink:label="us-gaap_GranteeStatusDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_GranteeStatusAxis" xlink:to="us-gaap_GranteeStatusDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedPaymentArrangementEmployeeMember" xlink:label="us-gaap_ShareBasedPaymentArrangementEmployeeMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_GranteeStatusDomain" xlink:to="us-gaap_ShareBasedPaymentArrangementEmployeeMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_CounterpartyNameAxis" xlink:label="srt_CounterpartyNameAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="2" xlink:from="us-gaap_OtherCommitmentsTable" xlink:to="srt_CounterpartyNameAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_RepurchaseAgreementCounterpartyNameDomain" xlink:label="srt_RepurchaseAgreementCounterpartyNameDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_CounterpartyNameAxis" xlink:to="srt_RepurchaseAgreementCounterpartyNameDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_Dr.SchaberMember" xlink:label="sngx_Dr.SchaberMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_RepurchaseAgreementCounterpartyNameDomain" xlink:to="sngx_Dr.SchaberMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" xlink:label="us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="3" xlink:from="us-gaap_OtherCommitmentsTable" xlink:to="us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:label="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" xlink:to="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ResearchAndDevelopmentArrangementMember" xlink:label="us-gaap_ResearchAndDevelopmentArrangementMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:to="us-gaap_ResearchAndDevelopmentArrangementMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_AssetPurchaseAgreementMember" xlink:label="sngx_AssetPurchaseAgreementMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:to="sngx_AssetPurchaseAgreementMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_StatementScenarioAxis" xlink:label="srt_StatementScenarioAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="4" xlink:from="us-gaap_OtherCommitmentsTable" xlink:to="srt_StatementScenarioAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ScenarioUnspecifiedDomain" xlink:label="srt_ScenarioUnspecifiedDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_StatementScenarioAxis" xlink:to="srt_ScenarioUnspecifiedDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_LeasePaymentsApplicableFromNovember2026ToOctober2027Member" xlink:label="sngx_LeasePaymentsApplicableFromNovember2026ToOctober2027Member" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_ScenarioUnspecifiedDomain" xlink:to="sngx_LeasePaymentsApplicableFromNovember2026ToOctober2027Member" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_LeasePaymentsApplicableFromNovember2027UntilExpirationMember" xlink:label="sngx_LeasePaymentsApplicableFromNovember2027UntilExpirationMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="srt_ScenarioUnspecifiedDomain" xlink:to="sngx_LeasePaymentsApplicableFromNovember2027UntilExpirationMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OtherCommitmentsLineItems" xlink:label="us-gaap_OtherCommitmentsLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="us-gaap_OtherCommitmentsTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ContractualObligation" xlink:label="us-gaap_ContractualObligation" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="us-gaap_ContractualObligation" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StockIssuedDuringPeriodSharesNewIssues" xlink:label="us-gaap_StockIssuedDuringPeriodSharesNewIssues" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="us-gaap_StockIssuedDuringPeriodSharesNewIssues" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_MilestonePaymentUponAttainmentOfApproval" xlink:label="sngx_MilestonePaymentUponAttainmentOfApproval" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="sngx_MilestonePaymentUponAttainmentOfApproval" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PaymentOfRoyaltyAndMilestoneAmounts" xlink:label="sngx_PaymentOfRoyaltyAndMilestoneAmounts" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="sngx_PaymentOfRoyaltyAndMilestoneAmounts" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PercentageOfOwnershipOutstandingStock" xlink:label="sngx_PercentageOfOwnershipOutstandingStock" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="sngx_PercentageOfOwnershipOutstandingStock" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_LeaseRentalPerMonth" xlink:label="sngx_LeaseRentalPerMonth" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="sngx_LeaseRentalPerMonth" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" xlink:label="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="8" xlink:from="us-gaap_OtherCommitmentsLineItems" xlink:to="us-gaap_ShareBasedCompensationArrangementByShareBasedPaymentAwardNumberOfSharesAuthorized" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureCommitmentsAndContingenciesMaturityDetails" xlink:type="extended" xlink:title="41002 - Disclosure - Commitments and Contingencies - Maturity (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongTermPurchaseCommitmentTable" xlink:label="us-gaap_LongTermPurchaseCommitmentTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" xlink:label="us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_LongTermPurchaseCommitmentTable" xlink:to="us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:label="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_LongTermPurchaseCommitmentByCategoryOfItemPurchasedAxis" xlink:to="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ResearchAndDevelopmentArrangementMember" xlink:label="us-gaap_ResearchAndDevelopmentArrangementMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:to="us-gaap_ResearchAndDevelopmentArrangementMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LeaseAgreementsMember" xlink:label="us-gaap_LeaseAgreementsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_LongTermPurchaseCommitmentCategoryOfItemPurchasedDomain" xlink:to="us-gaap_LeaseAgreementsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_LongTermPurchaseCommitmentLineItems" xlink:label="us-gaap_LongTermPurchaseCommitmentLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_LongTermPurchaseCommitmentLineItems" xlink:to="us-gaap_LongTermPurchaseCommitmentTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ContractualObligationFiscalYearMaturityScheduleAbstract" xlink:label="us-gaap_ContractualObligationFiscalYearMaturityScheduleAbstract" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_LongTermPurchaseCommitmentLineItems" xlink:to="us-gaap_ContractualObligationFiscalYearMaturityScheduleAbstract" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ContractualObligationDueInNextTwelveMonths" xlink:label="us-gaap_ContractualObligationDueInNextTwelveMonths" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_ContractualObligationFiscalYearMaturityScheduleAbstract" xlink:to="us-gaap_ContractualObligationDueInNextTwelveMonths" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ContractualObligationDueInSecondYear" xlink:label="us-gaap_ContractualObligationDueInSecondYear" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_ContractualObligationFiscalYearMaturityScheduleAbstract" xlink:to="us-gaap_ContractualObligationDueInSecondYear" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ContractualObligationDueInThirdYear" xlink:label="us-gaap_ContractualObligationDueInThirdYear" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_ContractualObligationFiscalYearMaturityScheduleAbstract" xlink:to="us-gaap_ContractualObligationDueInThirdYear" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ContractualObligationDueInFourthYear" xlink:label="us-gaap_ContractualObligationDueInFourthYear" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_ContractualObligationFiscalYearMaturityScheduleAbstract" xlink:to="us-gaap_ContractualObligationDueInFourthYear" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ContractualObligationDueInFifthYear" xlink:label="us-gaap_ContractualObligationDueInFifthYear" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_ContractualObligationFiscalYearMaturityScheduleAbstract" xlink:to="us-gaap_ContractualObligationDueInFifthYear" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ContractualObligation" xlink:label="us-gaap_ContractualObligation" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_ContractualObligationFiscalYearMaturityScheduleAbstract" xlink:to="us-gaap_ContractualObligation" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureOperatingSegmentsSegmentRevenuesAndProfitLossDetails" xlink:type="extended" xlink:title="41101 - Disclosure - Operating Segments - Segment Revenues and Profit (Loss) (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" xlink:label="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ConsolidationItemsAxis" xlink:label="srt_ConsolidationItemsAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" xlink:to="srt_ConsolidationItemsAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ConsolidationItemsDomain" xlink:label="srt_ConsolidationItemsDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_ConsolidationItemsAxis" xlink:to="srt_ConsolidationItemsDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingSegmentsMember" xlink:label="us-gaap_OperatingSegmentsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_ConsolidationItemsDomain" xlink:to="us-gaap_OperatingSegmentsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_MaterialReconcilingItemsMember" xlink:label="us-gaap_MaterialReconcilingItemsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="srt_ConsolidationItemsDomain" xlink:to="us-gaap_MaterialReconcilingItemsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CorporateNonSegmentMember" xlink:label="us-gaap_CorporateNonSegmentMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="srt_ConsolidationItemsDomain" xlink:to="us-gaap_CorporateNonSegmentMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_EliminationsAndReconcilingItemsMember" xlink:label="sngx_EliminationsAndReconcilingItemsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="srt_ConsolidationItemsDomain" xlink:to="sngx_EliminationsAndReconcilingItemsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementBusinessSegmentsAxis" xlink:label="us-gaap_StatementBusinessSegmentsAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="2" xlink:from="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" xlink:to="us-gaap_StatementBusinessSegmentsAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SegmentDomain" xlink:label="us-gaap_SegmentDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_StatementBusinessSegmentsAxis" xlink:to="us-gaap_SegmentDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PublicHealthSolutionsMember" xlink:label="sngx_PublicHealthSolutionsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_SegmentDomain" xlink:to="sngx_PublicHealthSolutionsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_BioTherapeuticsMember" xlink:label="sngx_BioTherapeuticsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_SegmentDomain" xlink:to="sngx_BioTherapeuticsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SegmentReportingInformationLineItems" xlink:label="us-gaap_SegmentReportingInformationLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NumberOfOperatingSegments" xlink:label="us-gaap_NumberOfOperatingSegments" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_NumberOfOperatingSegments" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_NumberOfReportableSegments" xlink:label="us-gaap_NumberOfReportableSegments" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_NumberOfReportableSegments" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_Revenues" xlink:label="us-gaap_Revenues" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_Revenues" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CostOfRevenue" xlink:label="us-gaap_CostOfRevenue" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_CostOfRevenue" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_GrossProfit" xlink:label="us-gaap_GrossProfit" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="6" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_GrossProfit" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ResearchAndDevelopmentExpense" xlink:label="us-gaap_ResearchAndDevelopmentExpense" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="7" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_ResearchAndDevelopmentExpense" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_GeneralAndAdministrativeExpense" xlink:label="us-gaap_GeneralAndAdministrativeExpense" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="8" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_GeneralAndAdministrativeExpense" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_AdjustedOperatingIncomeLoss" xlink:label="sngx_AdjustedOperatingIncomeLoss" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="9" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="sngx_AdjustedOperatingIncomeLoss" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ShareBasedCompensation" xlink:label="us-gaap_ShareBasedCompensation" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="10" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_ShareBasedCompensation" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_DepreciationDepletionAndAmortization" xlink:label="us-gaap_DepreciationDepletionAndAmortization" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="11" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_DepreciationDepletionAndAmortization" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingIncomeLoss" xlink:label="us-gaap_OperatingIncomeLoss" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="12" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_OperatingIncomeLoss" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_NonOperatingIncomeLossIncludingOneTimeGainLoss" xlink:label="sngx_NonOperatingIncomeLossIncludingOneTimeGainLoss" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="13" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="sngx_NonOperatingIncomeLossIncludingOneTimeGainLoss" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:label="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="14" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureOperatingSegmentsReconciliationToConsolidatedLossBeforeIncomeTaxesDetails" xlink:type="extended" xlink:title="41102 - Disclosure - Operating Segments - Reconciliation to Consolidated Loss Before Income Taxes (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" xlink:label="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ConsolidationItemsAxis" xlink:label="srt_ConsolidationItemsAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" xlink:to="srt_ConsolidationItemsAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ConsolidationItemsDomain" xlink:label="srt_ConsolidationItemsDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_ConsolidationItemsAxis" xlink:to="srt_ConsolidationItemsDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingSegmentsMember" xlink:label="us-gaap_OperatingSegmentsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_ConsolidationItemsDomain" xlink:to="us-gaap_OperatingSegmentsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CorporateNonSegmentMember" xlink:label="us-gaap_CorporateNonSegmentMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="srt_ConsolidationItemsDomain" xlink:to="us-gaap_CorporateNonSegmentMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SegmentReportingInformationLineItems" xlink:label="us-gaap_SegmentReportingInformationLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingIncomeLoss" xlink:label="us-gaap_OperatingIncomeLoss" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_OperatingIncomeLoss" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_InterestIncomeExpenseNonoperatingNet" xlink:label="us-gaap_InterestIncomeExpenseNonoperatingNet" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_InterestIncomeExpenseNonoperatingNet" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OtherNonoperatingIncomeExpense" xlink:label="us-gaap_OtherNonoperatingIncomeExpense" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_OtherNonoperatingIncomeExpense" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" xlink:label="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="5" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureOperatingSegmentsSegmentAssetsDetails" xlink:type="extended" xlink:title="41103 - Disclosure - Operating Segments - Segment Assets (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" xlink:label="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ConsolidationItemsAxis" xlink:label="srt_ConsolidationItemsAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" xlink:to="srt_ConsolidationItemsAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/srt/2024/elts/srt-2024.xsd#srt_ConsolidationItemsDomain" xlink:label="srt_ConsolidationItemsDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="srt_ConsolidationItemsAxis" xlink:to="srt_ConsolidationItemsDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_OperatingSegmentsMember" xlink:label="us-gaap_OperatingSegmentsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="srt_ConsolidationItemsDomain" xlink:to="us-gaap_OperatingSegmentsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_CorporateNonSegmentMember" xlink:label="us-gaap_CorporateNonSegmentMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="srt_ConsolidationItemsDomain" xlink:to="us-gaap_CorporateNonSegmentMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_StatementBusinessSegmentsAxis" xlink:label="us-gaap_StatementBusinessSegmentsAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="2" xlink:from="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" xlink:to="us-gaap_StatementBusinessSegmentsAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SegmentDomain" xlink:label="us-gaap_SegmentDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_StatementBusinessSegmentsAxis" xlink:to="us-gaap_SegmentDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_BioTherapeuticsMember" xlink:label="sngx_BioTherapeuticsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_SegmentDomain" xlink:to="sngx_BioTherapeuticsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_PublicHealthSolutionsMember" xlink:label="sngx_PublicHealthSolutionsMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_SegmentDomain" xlink:to="sngx_PublicHealthSolutionsMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SegmentReportingInformationLineItems" xlink:label="us-gaap_SegmentReportingInformationLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_ScheduleOfSegmentReportingInformationBySegmentTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_Assets" xlink:label="us-gaap_Assets" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_SegmentReportingInformationLineItems" xlink:to="us-gaap_Assets" priority="1" use="optional" />
  </definitionLink>
  <definitionLink xlink:role="http://soligenix.com/role/DisclosureSubsequentEventsDetails" xlink:type="extended" xlink:title="41201 - Disclosure - Subsequent Events (Details)" xmlns="http://www.xbrl.org/2003/linkbase">
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventTable" xlink:label="us-gaap_SubsequentEventTable" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventTypeAxis" xlink:label="us-gaap_SubsequentEventTypeAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="1" xlink:from="us-gaap_SubsequentEventTable" xlink:to="us-gaap_SubsequentEventTypeAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventTypeDomain" xlink:label="us-gaap_SubsequentEventTypeDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_SubsequentEventTypeAxis" xlink:to="us-gaap_SubsequentEventTypeDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventMember" xlink:label="us-gaap_SubsequentEventMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_SubsequentEventTypeDomain" xlink:to="us-gaap_SubsequentEventMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsidiarySaleOfStockAxis" xlink:label="us-gaap_SubsidiarySaleOfStockAxis" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" order="2" xlink:from="us-gaap_SubsequentEventTable" xlink:to="us-gaap_SubsidiarySaleOfStockAxis" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SaleOfStockNameOfTransactionDomain" xlink:label="us-gaap_SaleOfStockNameOfTransactionDomain" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" order="1" xlink:from="us-gaap_SubsidiarySaleOfStockAxis" xlink:to="us-gaap_SaleOfStockNameOfTransactionDomain" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_AtMarketIssuanceSalesMember" xlink:label="sngx_AtMarketIssuanceSalesMember" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="1" xlink:from="us-gaap_SaleOfStockNameOfTransactionDomain" xlink:to="sngx_AtMarketIssuanceSalesMember" use="optional" />
    <loc xlink:type="locator" xlink:href="https://xbrl.fasb.org/us-gaap/2024/elts/us-gaap-2024.xsd#us-gaap_SubsequentEventLineItems" xlink:label="us-gaap_SubsequentEventLineItems" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" order="1" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="us-gaap_SubsequentEventTable" use="optional" xbrldt:contextElement="segment" xbrldt:closed="true" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_ThresholdPercentageOfCompensationFromGrossProceeds" xlink:label="sngx_ThresholdPercentageOfCompensationFromGrossProceeds" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="2" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="sngx_ThresholdPercentageOfCompensationFromGrossProceeds" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_SaleOfStockAggregateValueOfSharesToBeIssuedInTransaction" xlink:label="sngx_SaleOfStockAggregateValueOfSharesToBeIssuedInTransaction" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="3" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="sngx_SaleOfStockAggregateValueOfSharesToBeIssuedInTransaction" priority="1" use="optional" />
    <loc xlink:type="locator" xlink:href="sngx-20251231.xsd#sngx_CommonStockValueOfSharesReservedForFutureIssuance" xlink:label="sngx_CommonStockValueOfSharesReservedForFutureIssuance" />
    <definitionArc xlink:type="arc" xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" order="4" xlink:from="us-gaap_SubsequentEventLineItems" xlink:to="sngx_CommonStockValueOfSharesReservedForFutureIssuance" priority="1" use="optional" />
  </definitionLink>
</link:linkbase>
