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

<!--XBRL Document Created with the Workiva Platform-->
<!--Copyright 2026 Workiva-->
<!--r:019ee04f-83ec-7eb4-bd58-3acf13764f94,g:864f0e9f-6790-4d77-a302-860488846c33-->
<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-20260806.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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityInformationLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntitiesTable_019ee04f-83ec-7dd4-932a-a20e789afb0a" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_EntitiesTable_019ee04f-83ec-7dd4-932a-a20e789afb0a" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressesAddressTypeAxis_019ee04f-83ec-7bc3-96dd-f6ccd533fb8a" 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_019ee04f-83ec-7dd4-932a-a20e789afb0a" xlink:to="loc_dei_EntityAddressesAddressTypeAxis_019ee04f-83ec-7bc3-96dd-f6ccd533fb8a" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AddressTypeDomain_019ee04f-83ec-7bc3-96dd-f6ccd533fb8a_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_019ee04f-83ec-7bc3-96dd-f6ccd533fb8a" xlink:to="loc_dei_AddressTypeDomain_019ee04f-83ec-7bc3-96dd-f6ccd533fb8a_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AddressTypeDomain_019ee04f-83ec-7f29-9a09-4a6457765227" 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_019ee04f-83ec-7bc3-96dd-f6ccd533fb8a" xlink:to="loc_dei_AddressTypeDomain_019ee04f-83ec-7f29-9a09-4a6457765227" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressStateOrProvince_019ee04f-83ec-79b4-b831-bff6d167199c" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_EntityAddressStateOrProvince_019ee04f-83ec-79b4-b831-bff6d167199c" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressCityOrTown_019ee04f-83ec-7a97-aec6-f2cbb2ec86cd" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_EntityAddressCityOrTown_019ee04f-83ec-7a97-aec6-f2cbb2ec86cd" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressPostalZipCode_019ee04f-83ec-7458-bac5-bf365ca7c079" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_EntityAddressPostalZipCode_019ee04f-83ec-7458-bac5-bf365ca7c079" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentType_019ee04f-83ec-7075-b26c-a87789a173ba" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_DocumentType_019ee04f-83ec-7075-b26c-a87789a173ba" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentPeriodEndDate_019ee04f-83ec-7598-898b-702714477483" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_DocumentPeriodEndDate_019ee04f-83ec-7598-898b-702714477483" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityRegistrantName_019ee04f-83ec-7a6b-95e1-26aabbd9d9c9" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_EntityRegistrantName_019ee04f-83ec-7a6b-95e1-26aabbd9d9c9" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityIncorporationStateCountryCode_019ee04f-83ec-7578-bd0b-5412456723f6" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_EntityIncorporationStateCountryCode_019ee04f-83ec-7578-bd0b-5412456723f6" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityFileNumber_019ee04f-83ec-7929-8bf0-8c18fbb402ca" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_EntityFileNumber_019ee04f-83ec-7929-8bf0-8c18fbb402ca" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityTaxIdentificationNumber_019ee04f-83ec-7afb-a2ad-6ba2acd735c9" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_EntityTaxIdentificationNumber_019ee04f-83ec-7afb-a2ad-6ba2acd735c9" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressAddressLine1_019ee04f-83ec-784e-ae87-6365252f6ff1" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_EntityAddressAddressLine1_019ee04f-83ec-784e-ae87-6365252f6ff1" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressCityOrTown_019ee04f-83ec-7b77-99e3-5037be233569" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityAddressCityOrTown"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressStateOrProvince_019ee04f-83ec-736e-aeab-44c87a7791e5" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityAddressStateOrProvince"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressPostalZipCode_019ee04f-83ec-7de1-a72a-9a66d343113e" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityAddressPostalZipCode"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_CityAreaCode_019ee04f-83ec-72fd-900e-3fcec0f04455" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_CityAreaCode_019ee04f-83ec-72fd-900e-3fcec0f04455" xlink:type="arc" order="13"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_LocalPhoneNumber_019ee04f-83ec-7d4b-859b-0465300ec604" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_LocalPhoneNumber_019ee04f-83ec-7d4b-859b-0465300ec604" xlink:type="arc" order="14"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_WrittenCommunications_019ee04f-83ec-7134-a27e-ae390c65eb69" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_WrittenCommunications_019ee04f-83ec-7134-a27e-ae390c65eb69" xlink:type="arc" order="15"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_SolicitingMaterial_019ee04f-83ec-7cf1-9abd-f32b906d989c" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_SolicitingMaterial_019ee04f-83ec-7cf1-9abd-f32b906d989c" xlink:type="arc" order="16"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_PreCommencementTenderOffer_019ee04f-83ec-7cc1-b8ec-8822c8f9210d" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_PreCommencementTenderOffer_019ee04f-83ec-7cc1-b8ec-8822c8f9210d" xlink:type="arc" order="17"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_PreCommencementIssuerTenderOffer_019ee04f-83ec-7d1d-9001-8c0eb9908f1a" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_PreCommencementIssuerTenderOffer_019ee04f-83ec-7d1d-9001-8c0eb9908f1a" xlink:type="arc" order="18"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_Security12bTitle_019ee04f-83ec-7701-8ad9-a778fbfb5001" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_Security12bTitle_019ee04f-83ec-7701-8ad9-a778fbfb5001" xlink:type="arc" order="19"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_TradingSymbol_019ee04f-83ec-7aad-b407-22731c35cb7b" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_TradingSymbol_019ee04f-83ec-7aad-b407-22731c35cb7b" xlink:type="arc" order="20"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityEmergingGrowthCompany_019ee04f-83ec-7687-aa60-fdd1957e587d" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_EntityEmergingGrowthCompany_019ee04f-83ec-7687-aa60-fdd1957e587d" xlink:type="arc" order="21"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityCentralIndexKey_019ee04f-83ec-7ff3-ab62-03cb07875cf2" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_EntityCentralIndexKey_019ee04f-83ec-7ff3-ab62-03cb07875cf2" xlink:type="arc" order="22"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AmendmentFlag_019ee04f-83ec-7f7d-939a-2df1c55bd218" 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_019ee04f-83ec-7d9d-8c9a-4d8db2a25b6c" xlink:to="loc_dei_AmendmentFlag_019ee04f-83ec-7f7d-939a-2df1c55bd218" xlink:type="arc" order="23"/>
  </link:definitionLink>
</link:linkbase>
