Background The role of carbohydrate antigen 19‐9 (CA 19‐9) in response assessment among patients with intrahepatic cholangiocarcinoma (iCCA) remains unknown. The authors studied the association of the CA 19‐9 response (defined as a reduction >50% from baseline) with the radiologic response and the outcome in patients with unresectable iCCA. Methods A prospective cohort of 422 patients who were initially diagnosed with unresectable iCCA, had baseline CA 19‐9 levels ≥100 U/mL, and received treatment with systemic therapies at the authors' institution between January 2017 and December 2021 were enrolled in this study. The radiologic response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. A landmark assessment of the CA 19‐9 response and the radiologic response was performed. The associations between CA 19‐9 response and imaging response, progression‐free survival (PFS), and overall survival (OS) were analyzed. Results Two hundred sixty‐seven patients (63.3%) had a CA 19‐9 response. A CA 19‐9 response was observed in 123 of 132 (93.2%) radiologic responders and in 144 of 290 (49.7%) radiologic nonresponders (p < .001). CA 19‐9 responders outperformed nonresponders in median PFS (10.6 vs. 3.6 months; hazard ratio HR, 4.8 months; 95% confidence interval CI, 3.8–6.0 months; p < .001) and OS (21.4 vs. 6.3 months; HR, 5.3 months; 95% CI, 4.2–6.7 months; p < .001). The common independent predictors of both OS and PFS included metastasis, CA 19‐9 nonresponder status, and radiologic nonresponder status in multivariable analysis. Conclusions CA 19‐9 response is a valuable addition to assess tumor response and is associated with improved outcomes in patients with iCCA. Achieving a CA 19‐9 response should be one of the therapeutic objectives of patients with iCCA after systemic therapies. Plain language summary A decline in carbohydrate antigen 19‐9 levels from elevated baseline levels should be one of the therapeutic aims of patients with intrahepatic cholangiocarcinoma who are managed with systemic therapies. Biomarkers for predicting treatment outcomes are an unmet need for patients with intrahepatic cholangiocarcinoma (iCCA) treated with systemic therapies. This article shows that the carbohydrate antigen 19‐9 response correlates with the radiologic response and outcome of patients with iCCA after treatment.