<?xml version="1.0" encoding="UTF-8"?>

<!--XBRL Document Created with the Workiva Platform-->
<!--Copyright 2026 Workiva-->
<!--r:019eadd9-35df-797b-bbe7-dd542938742f,g:d02993d9-a10c-4d89-8e04-31707dc68dd4-->
<link:linkbase xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xbrldt="http://xbrl.org/2005/xbrldt" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd">
  <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: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/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/domain-member" xlink:type="simple" xlink:href="http://www.xbrl.org/2005/xbrldt-2005.xsd#domain-member"/>
  <link:roleRef roleURI="http://www.avalotherapeutics.com/role/CoverPageDocument" xlink:type="simple" xlink:href="avtx-20260616.xsd#CoverPageDocument"/>
  <link:definitionLink xlink:role="http://www.avalotherapeutics.com/role/CoverPageDocument" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityInformationLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntitiesTable_019eadd9-35df-7aa8-9588-d9fa5961e869" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntitiesTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_EntitiesTable_019eadd9-35df-7aa8-9588-d9fa5961e869" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressesAddressTypeAxis_019eadd9-35df-72df-b7f4-78a1c0565dc5" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityAddressesAddressTypeAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_dei_EntitiesTable_019eadd9-35df-7aa8-9588-d9fa5961e869" xlink:to="loc_dei_EntityAddressesAddressTypeAxis_019eadd9-35df-72df-b7f4-78a1c0565dc5" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AddressTypeDomain_019eadd9-35df-72df-b7f4-78a1c0565dc5_default" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_AddressTypeDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_dei_EntityAddressesAddressTypeAxis_019eadd9-35df-72df-b7f4-78a1c0565dc5" xlink:to="loc_dei_AddressTypeDomain_019eadd9-35df-72df-b7f4-78a1c0565dc5_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AddressTypeDomain_019eadd9-35df-77cd-b5c8-77b7013ebccd" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_AddressTypeDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_dei_EntityAddressesAddressTypeAxis_019eadd9-35df-72df-b7f4-78a1c0565dc5" xlink:to="loc_dei_AddressTypeDomain_019eadd9-35df-77cd-b5c8-77b7013ebccd" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressStateOrProvince_019eadd9-35df-7201-995e-1a22a96bad08" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityAddressStateOrProvince"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_EntityAddressStateOrProvince_019eadd9-35df-7201-995e-1a22a96bad08" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressCityOrTown_019eadd9-35df-719a-ad29-93eb5a5be374" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityAddressCityOrTown"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_EntityAddressCityOrTown_019eadd9-35df-719a-ad29-93eb5a5be374" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressPostalZipCode_019eadd9-35df-717a-b311-5601ebe5bb16" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityAddressPostalZipCode"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_EntityAddressPostalZipCode_019eadd9-35df-717a-b311-5601ebe5bb16" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentType_019eadd9-35df-72ad-85a0-6f291f2ed9c4" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_DocumentType"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_DocumentType_019eadd9-35df-72ad-85a0-6f291f2ed9c4" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentPeriodEndDate_019eadd9-35df-7a7a-af44-e4c10b37ac75" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_DocumentPeriodEndDate"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_DocumentPeriodEndDate_019eadd9-35df-7a7a-af44-e4c10b37ac75" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityRegistrantName_019eadd9-35df-711f-adbf-5b93b5c6b401" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityRegistrantName"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_EntityRegistrantName_019eadd9-35df-711f-adbf-5b93b5c6b401" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityIncorporationStateCountryCode_019eadd9-35df-722f-ba25-b928de379fda" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityIncorporationStateCountryCode"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_EntityIncorporationStateCountryCode_019eadd9-35df-722f-ba25-b928de379fda" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityFileNumber_019eadd9-35df-7f3e-9e37-48c738b797ad" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityFileNumber"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_EntityFileNumber_019eadd9-35df-7f3e-9e37-48c738b797ad" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityTaxIdentificationNumber_019eadd9-35df-7abd-a595-f073e90dc9ef" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityTaxIdentificationNumber"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_EntityTaxIdentificationNumber_019eadd9-35df-7abd-a595-f073e90dc9ef" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressAddressLine1_019eadd9-35df-7632-9fc0-c073fa47f188" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityAddressAddressLine1"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_EntityAddressAddressLine1_019eadd9-35df-7632-9fc0-c073fa47f188" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressCityOrTown_019eadd9-35df-7de9-b603-76c7f64e2069" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityAddressCityOrTown"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressStateOrProvince_019eadd9-35df-7837-8aa3-71958ce89dc4" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityAddressStateOrProvince"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressPostalZipCode_019eadd9-35df-771f-8932-0e5f586bd824" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityAddressPostalZipCode"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_CityAreaCode_019eadd9-35df-7d26-b10f-34e232524a12" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_CityAreaCode"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_CityAreaCode_019eadd9-35df-7d26-b10f-34e232524a12" xlink:type="arc" order="13"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_LocalPhoneNumber_019eadd9-35df-7935-ad38-72b5193f67ba" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_LocalPhoneNumber"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_LocalPhoneNumber_019eadd9-35df-7935-ad38-72b5193f67ba" xlink:type="arc" order="14"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_WrittenCommunications_019eadd9-35df-7c1d-b526-690e03a4360d" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_WrittenCommunications"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_WrittenCommunications_019eadd9-35df-7c1d-b526-690e03a4360d" xlink:type="arc" order="15"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_SolicitingMaterial_019eadd9-35df-7a3c-8d32-01c35714ca97" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_SolicitingMaterial"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_SolicitingMaterial_019eadd9-35df-7a3c-8d32-01c35714ca97" xlink:type="arc" order="16"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_PreCommencementTenderOffer_019eadd9-35df-72b7-9a61-1a3a8aaa1ebe" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_PreCommencementTenderOffer"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_PreCommencementTenderOffer_019eadd9-35df-72b7-9a61-1a3a8aaa1ebe" xlink:type="arc" order="17"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_PreCommencementIssuerTenderOffer_019eadd9-35df-7759-8b04-08cdab7a75e6" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_PreCommencementIssuerTenderOffer"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_PreCommencementIssuerTenderOffer_019eadd9-35df-7759-8b04-08cdab7a75e6" xlink:type="arc" order="18"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_Security12bTitle_019eadd9-35df-734a-b3be-4c24b6633d13" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_Security12bTitle"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_Security12bTitle_019eadd9-35df-734a-b3be-4c24b6633d13" xlink:type="arc" order="19"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_TradingSymbol_019eadd9-35df-7cea-8cbb-c22d8e68f278" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_TradingSymbol"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_TradingSymbol_019eadd9-35df-7cea-8cbb-c22d8e68f278" xlink:type="arc" order="20"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityEmergingGrowthCompany_019eadd9-35df-77af-b877-055ef3dc92c1" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityEmergingGrowthCompany"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_EntityEmergingGrowthCompany_019eadd9-35df-77af-b877-055ef3dc92c1" xlink:type="arc" order="21"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityCentralIndexKey_019eadd9-35df-7aef-80b9-810f849834b4" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityCentralIndexKey"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_EntityCentralIndexKey_019eadd9-35df-7aef-80b9-810f849834b4" xlink:type="arc" order="22"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AmendmentFlag_019eadd9-35df-7251-aa79-915e615c1a02" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_AmendmentFlag"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_EntityInformationLineItems_019eadd9-35df-7353-b354-81e7311439dc" xlink:to="loc_dei_AmendmentFlag_019eadd9-35df-7251-aa79-915e615c1a02" xlink:type="arc" order="23"/>
  </link:definitionLink>
</link:linkbase>
