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Abstract Background Antipsychotic drugs (APDs) are used for treating mental illnesses and are also used by cancer patients. This study aimed to evaluate APD use in adult cancer patients who received radiotherapy (RT) in South Korea and assess the effects of APD use during RT on survival. Methods This retrospective cohort study utilized the National Health Insurance Service database database of Korea. We included adult cancer patients who underwent RT or chemotherapy (CTx, cisplatin, or 5-Fluorouracil) between 2010 and 2020. The APDs included in the analysis were aripiprazole, quetiapine, olanzapine, risperidone, haloperidol, and chlorpromazine. Results Overall, 725,897 patients received RT, and 115,500 received concomitant chemo-radiotherapy (CCRT). Of them, 41,118 (5.6%) took APDs during RT, and 8,129 (7%) took APDs during CCRT. Overall, 27,789 (67.58%) patients who took APDs during RT were men, and 28,004 (68.2%) were aged ≥ 60 years. The most frequently used APD during RT was quetiapine (64.93%). Patients who took APDs during RT and during CCRT had higher mortality rates (HR: 3.45 and 1.72, p |