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

<!--XBRL Document Created with the Workiva Platform-->
<!--Copyright 2026 Workiva-->
<!--r:019d1bfd-39ae-7145-8a46-ae003a6988f8,g:2e47da8e-61bd-4aec-88d7-2a044c0139f7-->
<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" xsi:schemaLocation="http://www.xbrl.org/2003/linkbase http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd">
  <link:arcroleRef arcroleURI="https://xbrl.org/2023/arcrole/summation-item" xlink:type="simple" xlink:href="https://www.xbrl.org/2023/calculation-1.1.xsd#summation-item"/>
  <link:roleRef roleURI="http://www.optimizerx.com/role/CONDENSEDCONSOLIDATEDBALANCESHEETS" xlink:type="simple" xlink:href="oprx-20260331.xsd#CONDENSEDCONSOLIDATEDBALANCESHEETS"/>
  <link:calculationLink xlink:role="http://www.optimizerx.com/role/CONDENSEDCONSOLIDATEDBALANCESHEETS" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_Assets_019d1bfd-39ae-7185-92cd-1fcf78a40c5a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_Assets"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherAssets_019d1bfd-39ae-7f8c-b40b-835db7703014" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherAssets"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_Assets_019d1bfd-39ae-7185-92cd-1fcf78a40c5a" xlink:to="loc_us-gaap_OtherAssets_019d1bfd-39ae-7f8c-b40b-835db7703014" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AssetsCurrent_019d1bfd-39ae-7f12-9def-2b4467dd31de" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AssetsCurrent"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_Assets_019d1bfd-39ae-7185-92cd-1fcf78a40c5a" xlink:to="loc_us-gaap_AssetsCurrent_019d1bfd-39ae-7f12-9def-2b4467dd31de" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PropertyPlantAndEquipmentNet_019d1bfd-39ae-7144-8fa2-455f60734873" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PropertyPlantAndEquipmentNet"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_Assets_019d1bfd-39ae-7185-92cd-1fcf78a40c5a" xlink:to="loc_us-gaap_PropertyPlantAndEquipmentNet_019d1bfd-39ae-7144-8fa2-455f60734873" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LiabilitiesAndStockholdersEquity_019d1bfd-39ae-7d4b-839e-305c31670bdd" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LiabilitiesAndStockholdersEquity"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockholdersEquity_019d1bfd-39ae-7139-ac56-1a052efdb37a" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockholdersEquity"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesAndStockholdersEquity_019d1bfd-39ae-7d4b-839e-305c31670bdd" xlink:to="loc_us-gaap_StockholdersEquity_019d1bfd-39ae-7139-ac56-1a052efdb37a" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_Liabilities_019d1bfd-39ae-72a2-ba52-5f1910ac9634" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_Liabilities"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesAndStockholdersEquity_019d1bfd-39ae-7d4b-839e-305c31670bdd" xlink:to="loc_us-gaap_Liabilities_019d1bfd-39ae-72a2-ba52-5f1910ac9634" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommitmentsAndContingencies_019d1bfd-39ae-70fb-a7c8-aa1fe3be269f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommitmentsAndContingencies"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesAndStockholdersEquity_019d1bfd-39ae-7d4b-839e-305c31670bdd" xlink:to="loc_us-gaap_CommitmentsAndContingencies_019d1bfd-39ae-70fb-a7c8-aa1fe3be269f" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherAssets_019d1bfd-39ae-71f7-9b68-4a1e95f90d09" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherAssets"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_Goodwill_019d1bfd-39ae-7a1b-b0a4-fed3744099d2" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_Goodwill"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_OtherAssets_019d1bfd-39ae-71f7-9b68-4a1e95f90d09" xlink:to="loc_us-gaap_Goodwill_019d1bfd-39ae-7a1b-b0a4-fed3744099d2" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_oprx_PatentRightsNet_019d1bfd-39ae-7c0b-85a2-9b48a1f3f07e" xlink:href="oprx-20260331.xsd#oprx_PatentRightsNet"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_OtherAssets_019d1bfd-39ae-71f7-9b68-4a1e95f90d09" xlink:to="loc_oprx_PatentRightsNet_019d1bfd-39ae-7c0b-85a2-9b48a1f3f07e" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_oprx_TechnologyAssetsNet_019d1bfd-39ae-7296-892c-41c9f135ff0e" xlink:href="oprx-20260331.xsd#oprx_TechnologyAssetsNet"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_OtherAssets_019d1bfd-39ae-71f7-9b68-4a1e95f90d09" xlink:to="loc_oprx_TechnologyAssetsNet_019d1bfd-39ae-7296-892c-41c9f135ff0e" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_oprx_CustomerRelationshipsNet_019d1bfd-39ae-739c-8c1d-6f3673e39220" xlink:href="oprx-20260331.xsd#oprx_CustomerRelationshipsNet"/>
    <link:calculationArc order="4" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_OtherAssets_019d1bfd-39ae-71f7-9b68-4a1e95f90d09" xlink:to="loc_oprx_CustomerRelationshipsNet_019d1bfd-39ae-739c-8c1d-6f3673e39220" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OperatingLeaseRightOfUseAsset_019d1bfd-39ae-7f2d-9e1b-6d245e447110" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingLeaseRightOfUseAsset"/>
    <link:calculationArc order="5" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_OtherAssets_019d1bfd-39ae-71f7-9b68-4a1e95f90d09" xlink:to="loc_us-gaap_OperatingLeaseRightOfUseAsset_019d1bfd-39ae-7f2d-9e1b-6d245e447110" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_oprx_OtherAssetsAndDeposits_019d1bfd-39ae-7dd4-a208-2f7c3d8e467f" xlink:href="oprx-20260331.xsd#oprx_OtherAssetsAndDeposits"/>
    <link:calculationArc order="6" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_OtherAssets_019d1bfd-39ae-71f7-9b68-4a1e95f90d09" xlink:to="loc_oprx_OtherAssetsAndDeposits_019d1bfd-39ae-7dd4-a208-2f7c3d8e467f" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LiabilitiesCurrent_019d1bfd-39ae-7e19-b52a-c8c2f0cf0e76" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LiabilitiesCurrent"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LongTermDebtCurrent_019d1bfd-39ae-719f-83e5-ddc62661d834" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LongTermDebtCurrent"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent_019d1bfd-39ae-7e19-b52a-c8c2f0cf0e76" xlink:to="loc_us-gaap_LongTermDebtCurrent_019d1bfd-39ae-719f-83e5-ddc62661d834" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AccountsPayableTradeCurrent_019d1bfd-39ae-7b9e-ab0a-0d28329a1310" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AccountsPayableTradeCurrent"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent_019d1bfd-39ae-7e19-b52a-c8c2f0cf0e76" xlink:to="loc_us-gaap_AccountsPayableTradeCurrent_019d1bfd-39ae-7b9e-ab0a-0d28329a1310" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AccruedLiabilitiesCurrent_019d1bfd-39ae-788e-bea4-26403254408b" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AccruedLiabilitiesCurrent"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent_019d1bfd-39ae-7e19-b52a-c8c2f0cf0e76" xlink:to="loc_us-gaap_AccruedLiabilitiesCurrent_019d1bfd-39ae-788e-bea4-26403254408b" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_oprx_RevenueSharePayableCurrent_019d1bfd-39ae-746b-8619-51e593c4ce68" xlink:href="oprx-20260331.xsd#oprx_RevenueSharePayableCurrent"/>
    <link:calculationArc order="4" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent_019d1bfd-39ae-7e19-b52a-c8c2f0cf0e76" xlink:to="loc_oprx_RevenueSharePayableCurrent_019d1bfd-39ae-746b-8619-51e593c4ce68" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OperatingLeaseLiabilityCurrent_019d1bfd-39ae-75c2-8db2-b003fa1ed772" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingLeaseLiabilityCurrent"/>
    <link:calculationArc order="5" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent_019d1bfd-39ae-7e19-b52a-c8c2f0cf0e76" xlink:to="loc_us-gaap_OperatingLeaseLiabilityCurrent_019d1bfd-39ae-75c2-8db2-b003fa1ed772" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ContractWithCustomerLiabilityCurrent_019d1bfd-39ae-73a3-9409-c20d16594d3d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ContractWithCustomerLiabilityCurrent"/>
    <link:calculationArc order="6" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LiabilitiesCurrent_019d1bfd-39ae-7e19-b52a-c8c2f0cf0e76" xlink:to="loc_us-gaap_ContractWithCustomerLiabilityCurrent_019d1bfd-39ae-73a3-9409-c20d16594d3d" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AssetsCurrent_019d1bfd-39ae-7587-b5d1-3d8e25781a6b" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AssetsCurrent"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CashAndCashEquivalentsAtCarryingValue_019d1bfd-39ae-7650-b6ea-70aa273f4c56" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CashAndCashEquivalentsAtCarryingValue"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_AssetsCurrent_019d1bfd-39ae-7587-b5d1-3d8e25781a6b" xlink:to="loc_us-gaap_CashAndCashEquivalentsAtCarryingValue_019d1bfd-39ae-7650-b6ea-70aa273f4c56" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AccountsReceivableNetCurrent_019d1bfd-39ae-748f-93f8-1a944b41a874" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AccountsReceivableNetCurrent"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_AssetsCurrent_019d1bfd-39ae-7587-b5d1-3d8e25781a6b" xlink:to="loc_us-gaap_AccountsReceivableNetCurrent_019d1bfd-39ae-748f-93f8-1a944b41a874" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeTaxesReceivable_019d1bfd-39ae-75f4-8861-2fb220f96d1d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeTaxesReceivable"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_AssetsCurrent_019d1bfd-39ae-7587-b5d1-3d8e25781a6b" xlink:to="loc_us-gaap_IncomeTaxesReceivable_019d1bfd-39ae-75f4-8861-2fb220f96d1d" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PrepaidExpenseCurrent_019d1bfd-39ae-7e23-ab91-b3f8a2f5bbfc" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PrepaidExpenseCurrent"/>
    <link:calculationArc order="4" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_AssetsCurrent_019d1bfd-39ae-7587-b5d1-3d8e25781a6b" xlink:to="loc_us-gaap_PrepaidExpenseCurrent_019d1bfd-39ae-7e23-ab91-b3f8a2f5bbfc" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_Liabilities_019d1bfd-39ae-7d53-bb09-58c2659c62f3" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_Liabilities"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DeferredIncomeTaxLiabilitiesNet_019d1bfd-39ae-7f2a-a90b-4714453d5f39" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DeferredIncomeTaxLiabilitiesNet"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_Liabilities_019d1bfd-39ae-7d53-bb09-58c2659c62f3" xlink:to="loc_us-gaap_DeferredIncomeTaxLiabilitiesNet_019d1bfd-39ae-7f2a-a90b-4714453d5f39" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OperatingLeaseLiabilityNoncurrent_019d1bfd-39ae-734e-af6e-055b3a0c3c14" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingLeaseLiabilityNoncurrent"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_Liabilities_019d1bfd-39ae-7d53-bb09-58c2659c62f3" xlink:to="loc_us-gaap_OperatingLeaseLiabilityNoncurrent_019d1bfd-39ae-734e-af6e-055b3a0c3c14" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LiabilitiesCurrent_019d1bfd-39ae-7a16-a86c-73f1ce549b36" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LiabilitiesCurrent"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_Liabilities_019d1bfd-39ae-7d53-bb09-58c2659c62f3" xlink:to="loc_us-gaap_LiabilitiesCurrent_019d1bfd-39ae-7a16-a86c-73f1ce549b36" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LongTermDebtNoncurrent_019d1bfd-39ae-74c1-aac8-fd176b5f8c41" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LongTermDebtNoncurrent"/>
    <link:calculationArc order="4" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_Liabilities_019d1bfd-39ae-7d53-bb09-58c2659c62f3" xlink:to="loc_us-gaap_LongTermDebtNoncurrent_019d1bfd-39ae-74c1-aac8-fd176b5f8c41" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_StockholdersEquity_019d1bfd-39ae-7dc6-8beb-b1bd72b7e481" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_StockholdersEquity"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CommonStockValue_019d1bfd-39ae-7a51-801d-c278bf54a662" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CommonStockValue"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity_019d1bfd-39ae-7dc6-8beb-b1bd72b7e481" xlink:to="loc_us-gaap_CommonStockValue_019d1bfd-39ae-7a51-801d-c278bf54a662" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AdditionalPaidInCapital_019d1bfd-39ae-742f-af0c-57bf2069ad0f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AdditionalPaidInCapital"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity_019d1bfd-39ae-7dc6-8beb-b1bd72b7e481" xlink:to="loc_us-gaap_AdditionalPaidInCapital_019d1bfd-39ae-742f-af0c-57bf2069ad0f" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_TreasuryStockValue_019d1bfd-39ae-7ff2-9d1a-1154b5319d4e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_TreasuryStockValue"/>
    <link:calculationArc order="3" weight="-1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity_019d1bfd-39ae-7dc6-8beb-b1bd72b7e481" xlink:to="loc_us-gaap_TreasuryStockValue_019d1bfd-39ae-7ff2-9d1a-1154b5319d4e" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_RetainedEarningsAccumulatedDeficit_019d1bfd-39ae-7a8f-aef8-2cddeb3415f7" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RetainedEarningsAccumulatedDeficit"/>
    <link:calculationArc order="4" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity_019d1bfd-39ae-7dc6-8beb-b1bd72b7e481" xlink:to="loc_us-gaap_RetainedEarningsAccumulatedDeficit_019d1bfd-39ae-7a8f-aef8-2cddeb3415f7" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PreferredStockValue_019d1bfd-39ae-7be0-b7ab-b16095eec705" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PreferredStockValue"/>
    <link:calculationArc order="5" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_StockholdersEquity_019d1bfd-39ae-7dc6-8beb-b1bd72b7e481" xlink:to="loc_us-gaap_PreferredStockValue_019d1bfd-39ae-7be0-b7ab-b16095eec705" xlink:type="arc"/>
  </link:calculationLink>
  <link:roleRef roleURI="http://www.optimizerx.com/role/CONDENSEDCONSOLIDATEDSTATEMENTSOFOPERATIONS" xlink:type="simple" xlink:href="oprx-20260331.xsd#CONDENSEDCONSOLIDATEDSTATEMENTSOFOPERATIONS"/>
  <link:calculationLink xlink:role="http://www.optimizerx.com/role/CONDENSEDCONSOLIDATEDSTATEMENTSOFOPERATIONS" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetIncomeLoss_019d1bfd-39ae-7b4c-91be-79bf0ef05760" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetIncomeLoss"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest_019d1bfd-39ae-73a5-a3a5-4588b91bc44c" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetIncomeLoss_019d1bfd-39ae-7b4c-91be-79bf0ef05760" xlink:to="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest_019d1bfd-39ae-73a5-a3a5-4588b91bc44c" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeTaxExpenseBenefit_019d1bfd-39ae-7ea5-83e8-097218a087fa" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeTaxExpenseBenefit"/>
    <link:calculationArc order="2" weight="-1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetIncomeLoss_019d1bfd-39ae-7b4c-91be-79bf0ef05760" xlink:to="loc_us-gaap_IncomeTaxExpenseBenefit_019d1bfd-39ae-7ea5-83e8-097218a087fa" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OperatingIncomeLoss_019d1bfd-39ae-72a2-aa92-8151e0d668b2" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingIncomeLoss"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_Revenues_019d1bfd-39ae-74de-9627-c98a33fa36a3" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_Revenues"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingIncomeLoss_019d1bfd-39ae-72a2-aa92-8151e0d668b2" xlink:to="loc_us-gaap_Revenues_019d1bfd-39ae-74de-9627-c98a33fa36a3" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CostsAndExpenses_019d1bfd-39ae-74a2-bc97-696a2b47824c" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CostsAndExpenses"/>
    <link:calculationArc order="2" weight="-1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_OperatingIncomeLoss_019d1bfd-39ae-72a2-aa92-8151e0d668b2" xlink:to="loc_us-gaap_CostsAndExpenses_019d1bfd-39ae-74a2-bc97-696a2b47824c" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest_019d1bfd-39ae-72a5-9c56-6282179c4d05" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OperatingIncomeLoss_019d1bfd-39ae-7ed0-a030-e94abb1ace88" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingIncomeLoss"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest_019d1bfd-39ae-72a5-9c56-6282179c4d05" xlink:to="loc_us-gaap_OperatingIncomeLoss_019d1bfd-39ae-7ed0-a030-e94abb1ace88" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NonoperatingIncomeExpense_019d1bfd-39ae-7e18-a2dc-c04a5fd96751" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NonoperatingIncomeExpense"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_IncomeLossFromContinuingOperationsBeforeIncomeTaxesExtraordinaryItemsNoncontrollingInterest_019d1bfd-39ae-72a5-9c56-6282179c4d05" xlink:to="loc_us-gaap_NonoperatingIncomeExpense_019d1bfd-39ae-7e18-a2dc-c04a5fd96751" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NonoperatingIncomeExpense_019d1bfd-39ae-74d2-93d3-253c4ada9ed1" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NonoperatingIncomeExpense"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_InterestExpenseNonoperating_019d1bfd-39ae-7e07-88d0-ebce7ca5d054" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_InterestExpenseNonoperating"/>
    <link:calculationArc order="1" weight="-1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NonoperatingIncomeExpense_019d1bfd-39ae-74d2-93d3-253c4ada9ed1" xlink:to="loc_us-gaap_InterestExpenseNonoperating_019d1bfd-39ae-7e07-88d0-ebce7ca5d054" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherNonoperatingIncome_019d1bfd-39ae-71b9-9822-db0a66476755" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherNonoperatingIncome"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NonoperatingIncomeExpense_019d1bfd-39ae-74d2-93d3-253c4ada9ed1" xlink:to="loc_us-gaap_OtherNonoperatingIncome_019d1bfd-39ae-71b9-9822-db0a66476755" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_InvestmentIncomeInterest_019d1bfd-39ae-702d-b45d-ad9bff6831a6" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_InvestmentIncomeInterest"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NonoperatingIncomeExpense_019d1bfd-39ae-74d2-93d3-253c4ada9ed1" xlink:to="loc_us-gaap_InvestmentIncomeInterest_019d1bfd-39ae-702d-b45d-ad9bff6831a6" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CostsAndExpenses_019d1bfd-39ae-79c6-9499-51ffa4bc4d5e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CostsAndExpenses"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_SellingAndMarketingExpense_019d1bfd-39ae-7933-8626-952f12555a25" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_SellingAndMarketingExpense"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_CostsAndExpenses_019d1bfd-39ae-79c6-9499-51ffa4bc4d5e" xlink:to="loc_us-gaap_SellingAndMarketingExpense_019d1bfd-39ae-7933-8626-952f12555a25" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_GeneralAndAdministrativeExpense_019d1bfd-39ae-73aa-85e9-9862da3a3a86" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_GeneralAndAdministrativeExpense"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_CostsAndExpenses_019d1bfd-39ae-79c6-9499-51ffa4bc4d5e" xlink:to="loc_us-gaap_GeneralAndAdministrativeExpense_019d1bfd-39ae-73aa-85e9-9862da3a3a86" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ResearchAndDevelopmentExpense_019dbaed-7d26-703f-aeb7-75e08079a99c" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ResearchAndDevelopmentExpense"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_CostsAndExpenses_019d1bfd-39ae-79c6-9499-51ffa4bc4d5e" xlink:to="loc_us-gaap_ResearchAndDevelopmentExpense_019dbaed-7d26-703f-aeb7-75e08079a99c" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AllocatedShareBasedCompensationExpense_019dbaed-7d26-718b-83eb-8877768fa7b0" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AllocatedShareBasedCompensationExpense"/>
    <link:calculationArc order="4" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_CostsAndExpenses_019d1bfd-39ae-79c6-9499-51ffa4bc4d5e" xlink:to="loc_us-gaap_AllocatedShareBasedCompensationExpense_019dbaed-7d26-718b-83eb-8877768fa7b0" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DepreciationAndAmortization_019dbaed-7d26-723a-a26d-7cdb3474f6e2" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DepreciationAndAmortization"/>
    <link:calculationArc order="5" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_CostsAndExpenses_019d1bfd-39ae-79c6-9499-51ffa4bc4d5e" xlink:to="loc_us-gaap_DepreciationAndAmortization_019dbaed-7d26-723a-a26d-7cdb3474f6e2" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CostOfRevenue_019e0487-1623-765d-a173-7c85e417f154" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CostOfRevenue"/>
    <link:calculationArc order="6" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_CostsAndExpenses_019d1bfd-39ae-79c6-9499-51ffa4bc4d5e" xlink:to="loc_us-gaap_CostOfRevenue_019e0487-1623-765d-a173-7c85e417f154" xlink:type="arc"/>
  </link:calculationLink>
  <link:roleRef roleURI="http://www.optimizerx.com/role/CONDENSEDCONSOLIDATEDSTATEMENTSOFCASHFLOWS" xlink:type="simple" xlink:href="oprx-20260331.xsd#CONDENSEDCONSOLIDATEDSTATEMENTSOFCASHFLOWS"/>
  <link:calculationLink xlink:role="http://www.optimizerx.com/role/CONDENSEDCONSOLIDATEDSTATEMENTSOFCASHFLOWS" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities_019d1bfd-39ae-710c-a28a-317147778ac9" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivities"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_RepaymentsOfLongTermDebt_019d1bfd-39ae-7be0-a10f-f2868b92eec8" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_RepaymentsOfLongTermDebt"/>
    <link:calculationArc order="1" weight="-1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities_019d1bfd-39ae-710c-a28a-317147778ac9" xlink:to="loc_us-gaap_RepaymentsOfLongTermDebt_019d1bfd-39ae-7be0-a10f-f2868b92eec8" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation_019d1bfd-39ae-76f3-8212-caffcb719bd2" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation"/>
    <link:calculationArc order="2" weight="-1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities_019d1bfd-39ae-710c-a28a-317147778ac9" xlink:to="loc_us-gaap_PaymentsRelatedToTaxWithholdingForShareBasedCompensation_019d1bfd-39ae-76f3-8212-caffcb719bd2" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities_019d1bfd-39ae-7af7-939f-448d645c58ec" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivities"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PaymentsToDevelopSoftware_019d1bfd-39ae-7ede-8791-c33122f90001" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PaymentsToDevelopSoftware"/>
    <link:calculationArc order="1" weight="-1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities_019d1bfd-39ae-7af7-939f-448d645c58ec" xlink:to="loc_us-gaap_PaymentsToDevelopSoftware_019d1bfd-39ae-7ede-8791-c33122f90001" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_PaymentsToAcquirePropertyPlantAndEquipment_019d1bfd-39ae-750f-91f3-0cb21486d4e3" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_PaymentsToAcquirePropertyPlantAndEquipment"/>
    <link:calculationArc order="2" weight="-1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities_019d1bfd-39ae-7af7-939f-448d645c58ec" xlink:to="loc_us-gaap_PaymentsToAcquirePropertyPlantAndEquipment_019d1bfd-39ae-750f-91f3-0cb21486d4e3" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivities"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ShareBasedCompensation_019d1bfd-39ae-7abf-b795-7c56e68ae17c" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ShareBasedCompensation"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_ShareBasedCompensation_019d1bfd-39ae-7abf-b795-7c56e68ae17c" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncreaseDecreaseInAccountsPayable_019d1bfd-39ae-7400-b391-cbefa02fcbdb" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInAccountsPayable"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_IncreaseDecreaseInAccountsPayable_019d1bfd-39ae-7400-b391-cbefa02fcbdb" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets_019d1bfd-39ae-7921-b535-73b8aeca83e4" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets"/>
    <link:calculationArc order="3" weight="-1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_IncreaseDecreaseInPrepaidDeferredExpenseAndOtherAssets_019d1bfd-39ae-7921-b535-73b8aeca83e4" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncreaseDecreaseInContractWithCustomerLiability_019d1bfd-39ae-7e94-855a-e69264363d82" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInContractWithCustomerLiability"/>
    <link:calculationArc order="4" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_IncreaseDecreaseInContractWithCustomerLiability_019d1bfd-39ae-7e94-855a-e69264363d82" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_AmortizationOfFinancingCosts_019d1bfd-39ae-7a47-b9db-b1c480447e37" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_AmortizationOfFinancingCosts"/>
    <link:calculationArc order="5" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_AmortizationOfFinancingCosts_019d1bfd-39ae-7a47-b9db-b1c480447e37" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_oprx_IncreaseDecreaseInRevenueSharePayable_019d1bfd-39ae-7926-95fd-4595dc1cf599" xlink:href="oprx-20260331.xsd#oprx_IncreaseDecreaseInRevenueSharePayable"/>
    <link:calculationArc order="6" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_oprx_IncreaseDecreaseInRevenueSharePayable_019d1bfd-39ae-7926-95fd-4595dc1cf599" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncreaseDecreaseInAccruedLiabilitiesAndOtherOperatingLiabilities_019d1bfd-39ae-7e43-8ed5-c4fd1fceb541" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInAccruedLiabilitiesAndOtherOperatingLiabilities"/>
    <link:calculationArc order="7" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_IncreaseDecreaseInAccruedLiabilitiesAndOtherOperatingLiabilities_019d1bfd-39ae-7e43-8ed5-c4fd1fceb541" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ProvisionForDoubtfulAccounts_019d1bfd-39ae-7f7e-88ce-c8f06c62b406" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ProvisionForDoubtfulAccounts"/>
    <link:calculationArc order="8" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_ProvisionForDoubtfulAccounts_019d1bfd-39ae-7f7e-88ce-c8f06c62b406" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncreaseDecreaseInAccruedTaxesPayable_019d1bfd-39ae-7e82-b78e-8ce6a1ff24e1" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInAccruedTaxesPayable"/>
    <link:calculationArc order="9" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_IncreaseDecreaseInAccruedTaxesPayable_019d1bfd-39ae-7e82-b78e-8ce6a1ff24e1" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_DepreciationAndAmortization_019d1bfd-39ae-7eb3-b5b3-f6c973104846" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_DepreciationAndAmortization"/>
    <link:calculationArc order="10" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_DepreciationAndAmortization_019d1bfd-39ae-7eb3-b5b3-f6c973104846" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetIncomeLoss_019d1bfd-39ae-75b2-9a23-c8eab1f6d0c8" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetIncomeLoss"/>
    <link:calculationArc order="11" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_NetIncomeLoss_019d1bfd-39ae-75b2-9a23-c8eab1f6d0c8" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncreaseDecreaseInAccountsReceivable_019d1bfd-39ae-7f8e-a924-07adca6b8675" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInAccountsReceivable"/>
    <link:calculationArc order="12" weight="-1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_IncreaseDecreaseInAccountsReceivable_019d1bfd-39ae-7f8e-a924-07adca6b8675" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncreaseDecreaseInDeferredIncomeTaxes_019d1bfd-39ae-73ad-8ac6-4c77ef74e0b0" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInDeferredIncomeTaxes"/>
    <link:calculationArc order="13" weight="-1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_IncreaseDecreaseInDeferredIncomeTaxes_019d1bfd-39ae-73ad-8ac6-4c77ef74e0b0" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_IncreaseDecreaseInOperatingLeaseLiability_019dbadc-2739-7335-948a-8ec42f6b84f3" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_IncreaseDecreaseInOperatingLeaseLiability"/>
    <link:calculationArc order="14" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7e3d-824f-fc558df5c246" xlink:to="loc_us-gaap_IncreaseDecreaseInOperatingLeaseLiability_019dbadc-2739-7335-948a-8ec42f6b84f3" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect_019d1bfd-39ae-7c8b-9bcc-4f865cdc1f7d" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7c2b-ac32-8dea8c683a20" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetCashProvidedByUsedInOperatingActivities"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect_019d1bfd-39ae-7c8b-9bcc-4f865cdc1f7d" xlink:to="loc_us-gaap_NetCashProvidedByUsedInOperatingActivities_019d1bfd-39ae-7c2b-ac32-8dea8c683a20" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities_019d1bfd-39ae-7d7c-a4b7-24388a7f1abb" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetCashProvidedByUsedInInvestingActivities"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect_019d1bfd-39ae-7c8b-9bcc-4f865cdc1f7d" xlink:to="loc_us-gaap_NetCashProvidedByUsedInInvestingActivities_019d1bfd-39ae-7d7c-a4b7-24388a7f1abb" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities_019d1bfd-39ae-73a4-9a52-ea71bf2dbab0" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_NetCashProvidedByUsedInFinancingActivities"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_CashCashEquivalentsRestrictedCashAndRestrictedCashEquivalentsPeriodIncreaseDecreaseIncludingExchangeRateEffect_019d1bfd-39ae-7c8b-9bcc-4f865cdc1f7d" xlink:to="loc_us-gaap_NetCashProvidedByUsedInFinancingActivities_019d1bfd-39ae-73a4-9a52-ea71bf2dbab0" xlink:type="arc"/>
  </link:calculationLink>
  <link:roleRef roleURI="http://www.optimizerx.com/role/GOODWILLANDINTANGIBLEASSETSScheduleofintangibleassetsincludedontheconsolidatedbalancesheetDetails" xlink:type="simple" xlink:href="oprx-20260331.xsd#GOODWILLANDINTANGIBLEASSETSScheduleofintangibleassetsincludedontheconsolidatedbalancesheetDetails"/>
  <link:calculationLink xlink:role="http://www.optimizerx.com/role/GOODWILLANDINTANGIBLEASSETSScheduleofintangibleassetsincludedontheconsolidatedbalancesheetDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019e00ac-a2cb-758d-8eca-684faa031a1c" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsNet"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization_019e00ac-a2cb-7553-8bdf-f8b4e5bb68b7" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization"/>
    <link:calculationArc order="1" weight="-1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019e00ac-a2cb-758d-8eca-684faa031a1c" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAccumulatedAmortization_019e00ac-a2cb-7553-8bdf-f8b4e5bb68b7" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsGross_019e00ac-a2cb-7794-963a-c49ec7f293de" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsGross"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019e00ac-a2cb-758d-8eca-684faa031a1c" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsGross_019e00ac-a2cb-7794-963a-c49ec7f293de" xlink:type="arc"/>
  </link:calculationLink>
  <link:roleRef roleURI="http://www.optimizerx.com/role/GOODWILLANDINTANGIBLEASSETSScheduleoffutureamortizationexpensesofintangiblesassetsDetails" xlink:type="simple" xlink:href="oprx-20260331.xsd#GOODWILLANDINTANGIBLEASSETSScheduleoffutureamortizationexpensesofintangiblesassetsDetails"/>
  <link:calculationLink xlink:role="http://www.optimizerx.com/role/GOODWILLANDINTANGIBLEASSETSScheduleoffutureamortizationexpensesofintangiblesassetsDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019e00ac-f9ba-7f31-b4d8-0ff4b038af4f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsNet"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths_019e00ac-f9ba-72ad-9161-9b69715b8481" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019e00ac-f9ba-7f31-b4d8-0ff4b038af4f" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseNextTwelveMonths_019e00ac-f9ba-72ad-9161-9b69715b8481" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo_019e00ac-f9ba-7189-b406-63b4b2fdb5f9" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019e00ac-f9ba-7f31-b4d8-0ff4b038af4f" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearTwo_019e00ac-f9ba-7189-b406-63b4b2fdb5f9" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree_019e00ac-f9ba-7edc-8ad0-c94f6a1fce45" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019e00ac-f9ba-7f31-b4d8-0ff4b038af4f" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearThree_019e00ac-f9ba-7edc-8ad0-c94f6a1fce45" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour_019e00ac-f9ba-7c4b-9de6-ba9976b684ea" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour"/>
    <link:calculationArc order="4" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019e00ac-f9ba-7f31-b4d8-0ff4b038af4f" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFour_019e00ac-f9ba-7c4b-9de6-ba9976b684ea" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive_019e00ac-f9ba-7d91-a0e5-4230d9e3e7d8" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive"/>
    <link:calculationArc order="5" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019e00ac-f9ba-7f31-b4d8-0ff4b038af4f" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseYearFive_019e00ac-f9ba-7d91-a0e5-4230d9e3e7d8" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseAfterYearFive_019e00ac-f9ba-71e6-8d59-a1fced851722" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseAfterYearFive"/>
    <link:calculationArc order="6" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_FiniteLivedIntangibleAssetsNet_019e00ac-f9ba-7f31-b4d8-0ff4b038af4f" xlink:to="loc_us-gaap_FiniteLivedIntangibleAssetsAmortizationExpenseAfterYearFive_019e00ac-f9ba-71e6-8d59-a1fced851722" xlink:type="arc"/>
  </link:calculationLink>
  <link:roleRef roleURI="http://www.optimizerx.com/role/LONGTERMDEBTSummaryofMaturitiesDetails" xlink:type="simple" xlink:href="oprx-20260331.xsd#LONGTERMDEBTSummaryofMaturitiesDetails"/>
  <link:calculationLink xlink:role="http://www.optimizerx.com/role/LONGTERMDEBTSummaryofMaturitiesDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LongTermDebt_019d1bfd-39ae-7d32-bc3b-c27f87c40b6f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LongTermDebt"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalRemainderOfFiscalYear_019d1bfd-39ae-744e-8904-df7250ea8666" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalRemainderOfFiscalYear"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LongTermDebt_019d1bfd-39ae-7d32-bc3b-c27f87c40b6f" xlink:to="loc_us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalRemainderOfFiscalYear_019d1bfd-39ae-744e-8904-df7250ea8666" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInNextTwelveMonths_019d1bfd-39ae-7358-9a39-f33b8c068a3e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInNextTwelveMonths"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LongTermDebt_019d1bfd-39ae-7d32-bc3b-c27f87c40b6f" xlink:to="loc_us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInNextTwelveMonths_019d1bfd-39ae-7358-9a39-f33b8c068a3e" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInYearTwo_019d1bfd-39ae-765e-b08c-8e981485c81b" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInYearTwo"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LongTermDebt_019d1bfd-39ae-7d32-bc3b-c27f87c40b6f" xlink:to="loc_us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInYearTwo_019d1bfd-39ae-765e-b08c-8e981485c81b" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInYearThree_019e00b5-3903-7def-a8c3-7f89f65d7664" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInYearThree"/>
    <link:calculationArc order="4" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LongTermDebt_019d1bfd-39ae-7d32-bc3b-c27f87c40b6f" xlink:to="loc_us-gaap_LongTermDebtMaturitiesRepaymentsOfPrincipalInYearThree_019e00b5-3903-7def-a8c3-7f89f65d7664" xlink:type="arc"/>
  </link:calculationLink>
  <link:roleRef roleURI="http://www.optimizerx.com/role/LEASESScheduleofcompanysleasecostDetails" xlink:type="simple" xlink:href="oprx-20260331.xsd#LEASESScheduleofcompanysleasecostDetails"/>
  <link:calculationLink xlink:role="http://www.optimizerx.com/role/LEASESScheduleofcompanysleasecostDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LeaseCost_019d1bfd-3a87-7463-94e4-d2a9020b9b3b" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LeaseCost"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_ShortTermLeaseCost_019d1bfd-3a87-714b-bb0c-e9018d75f2b5" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_ShortTermLeaseCost"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LeaseCost_019d1bfd-3a87-7463-94e4-d2a9020b9b3b" xlink:to="loc_us-gaap_ShortTermLeaseCost_019d1bfd-3a87-714b-bb0c-e9018d75f2b5" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OperatingLeaseCost_019d1bfd-3a87-7b67-8787-31b918e401f1" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingLeaseCost"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LeaseCost_019d1bfd-3a87-7463-94e4-d2a9020b9b3b" xlink:to="loc_us-gaap_OperatingLeaseCost_019d1bfd-3a87-7b67-8787-31b918e401f1" xlink:type="arc"/>
  </link:calculationLink>
  <link:roleRef roleURI="http://www.optimizerx.com/role/LEASESScheduleoffutureminimumleasepaymentsDetails" xlink:type="simple" xlink:href="oprx-20260331.xsd#LEASESScheduleoffutureminimumleasepaymentsDetails"/>
  <link:calculationLink xlink:role="http://www.optimizerx.com/role/LEASESScheduleoffutureminimumleasepaymentsDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue_019d1bfd-3a87-7de0-aeb7-ce6243f5f8f2" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsRemainderOfFiscalYear_019d1bfd-3a87-7952-8aaa-c253f2baf763" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsRemainderOfFiscalYear"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue_019d1bfd-3a87-7de0-aeb7-ce6243f5f8f2" xlink:to="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsRemainderOfFiscalYear_019d1bfd-3a87-7952-8aaa-c253f2baf763" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths_019d1bfd-3a87-73cc-95a5-fe183f413719" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue_019d1bfd-3a87-7de0-aeb7-ce6243f5f8f2" xlink:to="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueNextTwelveMonths_019d1bfd-3a87-73cc-95a5-fe183f413719" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo_019d1bfd-3a87-7cfd-81b6-67b825c78d14" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue_019d1bfd-3a87-7de0-aeb7-ce6243f5f8f2" xlink:to="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDueYearTwo_019d1bfd-3a87-7cfd-81b6-67b825c78d14" xlink:type="arc"/>
  </link:calculationLink>
  <link:roleRef roleURI="http://www.optimizerx.com/role/LEASESScheduleoffutureminimumleasepaymentsDetails_1" xlink:type="simple" xlink:href="oprx-20260331.xsd#LEASESScheduleoffutureminimumleasepaymentsDetails_1"/>
  <link:calculationLink xlink:role="http://www.optimizerx.com/role/LEASESScheduleoffutureminimumleasepaymentsDetails_1" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue_019d1bfd-3a87-7842-a444-ea4dd1fb7347" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount_019d1bfd-3a87-7dd5-a7b7-58a764448486" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue_019d1bfd-3a87-7842-a444-ea4dd1fb7347" xlink:to="loc_us-gaap_LesseeOperatingLeaseLiabilityUndiscountedExcessAmount_019d1bfd-3a87-7dd5-a7b7-58a764448486" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OperatingLeaseLiability_019d1bfd-3a87-758c-8f34-30d1c2094fa7" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OperatingLeaseLiability"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_LesseeOperatingLeaseLiabilityPaymentsDue_019d1bfd-3a87-7842-a444-ea4dd1fb7347" xlink:to="loc_us-gaap_OperatingLeaseLiability_019d1bfd-3a87-758c-8f34-30d1c2094fa7" xlink:type="arc"/>
  </link:calculationLink>
  <link:roleRef roleURI="http://www.optimizerx.com/role/LOSSPERSHAREScheduleofbasicanddilutedearningslosspershareDetails" xlink:type="simple" xlink:href="oprx-20260331.xsd#LOSSPERSHAREScheduleofbasicanddilutedearningslosspershareDetails"/>
  <link:calculationLink xlink:role="http://www.optimizerx.com/role/LOSSPERSHAREScheduleofbasicanddilutedearningslosspershareDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_019d1bfd-3a87-7092-b624-e11764044296" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustment_019d1bfd-3a87-72fa-8145-6696d6dd2d06" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustment"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_019d1bfd-3a87-7092-b624-e11764044296" xlink:to="loc_us-gaap_WeightedAverageNumberDilutedSharesOutstandingAdjustment_019d1bfd-3a87-72fa-8145-6696d6dd2d06" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_019d1bfd-3a87-71a6-aad0-f3aab5aa2590" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_WeightedAverageNumberOfSharesOutstandingBasic"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_WeightedAverageNumberOfDilutedSharesOutstanding_019d1bfd-3a87-7092-b624-e11764044296" xlink:to="loc_us-gaap_WeightedAverageNumberOfSharesOutstandingBasic_019d1bfd-3a87-71a6-aad0-f3aab5aa2590" xlink:type="arc"/>
  </link:calculationLink>
  <link:roleRef roleURI="http://www.optimizerx.com/role/COMMITMENTSANDCONTINGENCIESNarrativeDetails" xlink:type="simple" xlink:href="oprx-20260331.xsd#COMMITMENTSANDCONTINGENCIESNarrativeDetails"/>
  <link:calculationLink xlink:role="http://www.optimizerx.com/role/COMMITMENTSANDCONTINGENCIESNarrativeDetails" xlink:type="extended">
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherCommitment_019d1bfd-3a87-7fdf-b8f9-93ff34e3085e" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherCommitment"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherCommitmentDueInSecondYear_019d1bfd-3a87-776d-9838-02cacb60d923" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherCommitmentDueInSecondYear"/>
    <link:calculationArc order="1" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_OtherCommitment_019d1bfd-3a87-7fdf-b8f9-93ff34e3085e" xlink:to="loc_us-gaap_OtherCommitmentDueInSecondYear_019d1bfd-3a87-776d-9838-02cacb60d923" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherCommitmentsFutureMinimumPaymentsRemainderOfFiscalYear_019d1bfd-3a87-7227-afc0-9c7c40716e15" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherCommitmentsFutureMinimumPaymentsRemainderOfFiscalYear"/>
    <link:calculationArc order="2" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_OtherCommitment_019d1bfd-3a87-7fdf-b8f9-93ff34e3085e" xlink:to="loc_us-gaap_OtherCommitmentsFutureMinimumPaymentsRemainderOfFiscalYear_019d1bfd-3a87-7227-afc0-9c7c40716e15" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherCommitmentDueInNextTwelveMonths_019d1bfd-3a87-7c71-b64f-3d0181737832" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherCommitmentDueInNextTwelveMonths"/>
    <link:calculationArc order="3" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_OtherCommitment_019d1bfd-3a87-7fdf-b8f9-93ff34e3085e" xlink:to="loc_us-gaap_OtherCommitmentDueInNextTwelveMonths_019d1bfd-3a87-7c71-b64f-3d0181737832" xlink:type="arc"/>
    <link:loc xlink:type="locator" xlink:label="loc_us-gaap_OtherCommitmentDueInThirdYear_019e00b5-cff1-7aba-8669-5d23bfa2cf5f" xlink:href="https://xbrl.fasb.org/us-gaap/2025/elts/us-gaap-2025.xsd#us-gaap_OtherCommitmentDueInThirdYear"/>
    <link:calculationArc order="4" weight="1.0" xlink:arcrole="https://xbrl.org/2023/arcrole/summation-item" xlink:from="loc_us-gaap_OtherCommitment_019d1bfd-3a87-7fdf-b8f9-93ff34e3085e" xlink:to="loc_us-gaap_OtherCommitmentDueInThirdYear_019e00b5-cff1-7aba-8669-5d23bfa2cf5f" xlink:type="arc"/>
  </link:calculationLink>
</link:linkbase>
