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

<!--XBRL Document Created with the Workiva Platform-->
<!--Copyright 2026 Workiva-->
<!--r:01a0861b-1725-7ff1-b0d0-a4227009c412,g:11dc486a-b5af-41ec-af91-48efb34d4e13-->
<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://xerispharma.com/role/Cover" xlink:type="simple" xlink:href="xers-20260909.xsd#Cover"/>
  <link:definitionLink xlink:role="http://xerispharma.com/role/Cover" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_DocumentInformationLineItems"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentInformationTable_01a0861b-1725-73ce-96a2-af5fab5729d4" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_DocumentInformationTable"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/all" xlink:from="loc_dei_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_DocumentInformationTable_01a0861b-1725-73ce-96a2-af5fab5729d4" xlink:type="arc" order="1" xbrldt:closed="true" xbrldt:contextElement="segment"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentInformationDocumentAxis_01a0861b-1725-7437-a51b-8e0b0c3ac74e" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_DocumentInformationDocumentAxis"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/hypercube-dimension" xlink:from="loc_dei_DocumentInformationTable_01a0861b-1725-73ce-96a2-af5fab5729d4" xlink:to="loc_dei_DocumentInformationDocumentAxis_01a0861b-1725-7437-a51b-8e0b0c3ac74e" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentDomain_01a0861b-1725-7437-a51b-8e0b0c3ac74e_default" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_DocumentDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-default" xlink:from="loc_dei_DocumentInformationDocumentAxis_01a0861b-1725-7437-a51b-8e0b0c3ac74e" xlink:to="loc_dei_DocumentDomain_01a0861b-1725-7437-a51b-8e0b0c3ac74e_default" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentDomain_01a0861b-1725-7966-b9c5-f864895f3d8a" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_DocumentDomain"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/dimension-domain" xlink:from="loc_dei_DocumentInformationDocumentAxis_01a0861b-1725-7437-a51b-8e0b0c3ac74e" xlink:to="loc_dei_DocumentDomain_01a0861b-1725-7966-b9c5-f864895f3d8a" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentType_01a0861b-1725-734a-89ff-2b47a3871e80" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_DocumentType_01a0861b-1725-734a-89ff-2b47a3871e80" xlink:type="arc" order="0"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_DocumentPeriodEndDate_01a0861b-1725-7575-ad18-9e9a4da7f52a" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_DocumentPeriodEndDate_01a0861b-1725-7575-ad18-9e9a4da7f52a" xlink:type="arc" order="1"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityRegistrantName_01a0861b-1725-7116-9d39-9ebb1903304b" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_EntityRegistrantName_01a0861b-1725-7116-9d39-9ebb1903304b" xlink:type="arc" order="2"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityIncorporationStateCountryCode_01a0861b-1725-7730-9d23-9276842ebfdc" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_EntityIncorporationStateCountryCode_01a0861b-1725-7730-9d23-9276842ebfdc" xlink:type="arc" order="3"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityFileNumber_01a0861b-1725-7297-b65a-22b759b8e001" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_EntityFileNumber_01a0861b-1725-7297-b65a-22b759b8e001" xlink:type="arc" order="4"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityTaxIdentificationNumber_01a0861b-1725-73f6-ab1e-783cc84fef0e" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_EntityTaxIdentificationNumber_01a0861b-1725-73f6-ab1e-783cc84fef0e" xlink:type="arc" order="5"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressAddressLine1_01a0861b-1725-73ce-b4ea-5af845e8391d" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_EntityAddressAddressLine1_01a0861b-1725-73ce-b4ea-5af845e8391d" xlink:type="arc" order="6"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressAddressLine2_01a0861b-1725-7ebc-87b9-2eed27dc988a" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_EntityAddressAddressLine2"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_EntityAddressAddressLine2_01a0861b-1725-7ebc-87b9-2eed27dc988a" xlink:type="arc" order="7"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressCityOrTown_01a0861b-1725-76fa-91e9-79bce372a82b" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_EntityAddressCityOrTown_01a0861b-1725-76fa-91e9-79bce372a82b" xlink:type="arc" order="8"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressStateOrProvince_01a0861b-1725-7540-b60f-4a20d37228f1" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_EntityAddressStateOrProvince_01a0861b-1725-7540-b60f-4a20d37228f1" xlink:type="arc" order="9"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityAddressPostalZipCode_01a0861b-1725-7e18-8e3b-786ee7a519aa" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_EntityAddressPostalZipCode_01a0861b-1725-7e18-8e3b-786ee7a519aa" xlink:type="arc" order="10"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_CityAreaCode_01a0861b-1725-798a-a111-46a2d7b114fd" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_CityAreaCode_01a0861b-1725-798a-a111-46a2d7b114fd" xlink:type="arc" order="11"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_LocalPhoneNumber_01a0861b-1725-70e4-b07d-252c752b9374" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_LocalPhoneNumber_01a0861b-1725-70e4-b07d-252c752b9374" xlink:type="arc" order="12"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_WrittenCommunications_01a0861b-1725-7e0e-9fda-0b48b7420f7d" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_WrittenCommunications_01a0861b-1725-7e0e-9fda-0b48b7420f7d" xlink:type="arc" order="13"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_SolicitingMaterial_01a0861b-1725-7ba1-87ce-0ca474a00282" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_SolicitingMaterial_01a0861b-1725-7ba1-87ce-0ca474a00282" xlink:type="arc" order="14"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_PreCommencementTenderOffer_01a0861b-1725-7eb0-bb48-308468ee2160" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_PreCommencementTenderOffer_01a0861b-1725-7eb0-bb48-308468ee2160" xlink:type="arc" order="15"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_PreCommencementIssuerTenderOffer_01a0861b-1725-70f7-85f4-e0941f0653d1" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_PreCommencementIssuerTenderOffer_01a0861b-1725-70f7-85f4-e0941f0653d1" xlink:type="arc" order="16"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_Security12bTitle_01a0861b-1725-7a12-b1e0-23a28eb079b6" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_Security12bTitle_01a0861b-1725-7a12-b1e0-23a28eb079b6" xlink:type="arc" order="17"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_TradingSymbol_01a0861b-1725-78b5-991a-1a45bdd8cf51" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_TradingSymbol_01a0861b-1725-78b5-991a-1a45bdd8cf51" xlink:type="arc" order="18"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_SecurityExchangeName_01a0861b-1725-7e79-9811-03aa02312a97" xlink:href="https://xbrl.sec.gov/dei/2026/dei-2026.xsd#dei_SecurityExchangeName"/>
    <link:definitionArc xlink:arcrole="http://xbrl.org/int/dim/arcrole/domain-member" xlink:from="loc_dei_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_SecurityExchangeName_01a0861b-1725-7e79-9811-03aa02312a97" xlink:type="arc" order="19"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityEmergingGrowthCompany_01a0861b-1725-7b2a-be12-da33e50ff215" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_EntityEmergingGrowthCompany_01a0861b-1725-7b2a-be12-da33e50ff215" xlink:type="arc" order="20"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_AmendmentFlag_01a0861b-1725-7b3d-ac7d-6b7bd36f938f" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_AmendmentFlag_01a0861b-1725-7b3d-ac7d-6b7bd36f938f" xlink:type="arc" order="21"/>
    <link:loc xlink:type="locator" xlink:label="loc_dei_EntityCentralIndexKey_01a0861b-1725-73a4-abab-d7d8b475fa71" 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_DocumentInformationLineItems_01a0861b-1725-768b-b8dd-b88fcd5ca226" xlink:to="loc_dei_EntityCentralIndexKey_01a0861b-1725-73a4-abab-d7d8b475fa71" xlink:type="arc" order="22"/>
  </link:definitionLink>
</link:linkbase>
