Background Polypharmacy is an important issue in the care of older patients with cancer, as it increases the risk of unfavorable outcomes. We estimated the prevalence of polypharmacy, potentially inappropriate medication (PIM) use, and drug–drug interactions (DDIs) in older patients with cancer in Korea and their associations with clinical outcomes. Subjects, Materials, and Methods This was a secondary analysis of a prospective observational study of geriatric patients with cancer undergoing first‐line palliative chemotherapy. Eligible patients were older adults (≥70 years) with histologically diagnosed solid cancer who were candidates for first‐line palliative chemotherapy. All patients enrolled in this study received a geriatric assessment (GA) at baseline. We reviewed the daily medications taken by patients at the time of GA before starting chemotherapy. PIMs were assessed according to the 2015 Beers criteria, and DDIs were assessed by a clinical pharmacist using Lexi‐comp Drug Interactions. We evaluated the association between polypharmacy and clinical outcomes including treatment‐related toxicity, and hospitalization using logistic regression and Cox regression analyses. Results In total, 301 patients (median age 75 years; range, 70–93) were enrolled; the most common cancer types were colorectal cancer (28.9%) and lung cancer (24.6%). Mean number of daily medications was 4.7 (±3.1; range, 0–14). The prevalence of polypharmacy (≥5 medications) was 45.2% and that of excessive polypharmacy (≥10 medications) was 8.6%. PIM use was detected in 137 (45.5%) patients. Clinically significant DDIs were detected in 92 (30.6%) patients. Polypharmacy was significantly associated with hospitalization or emergency room (ER) visits (odds ratio: 1.73 1.18–2.55, p < .01). Neither polypharmacy nor PIM use showed association with treatment‐related toxicity. Conclusion Polypharmacy, PIM use, and potential major DDIs were prevalent in Korean geriatric patients with cancer. Polypharmacy was associated with a higher risk of hospitalization or ER visits during the chemotherapy period. Implications for Practice This study, which included 301 older Korean patients with cancer, highlights the increased prevalence of polypharmacy in this population planning to receive palliative chemotherapy. The prevalence of polypharmacy and excessive polypharmacy was 45.2% and 8.6%, respectively. The prescription of potentially inappropriate medications (PIMs) was detected in 45.5% and clinically significant drug–drug interaction in 30.6% of patients. Given the association of polypharmacy with increased hospitalization or emergency room visits, this study points to the need for increased awareness and intervention to minimize polypharmacy in the geriatric cancer population undergoing chemotherapy. Moreover, specific criteria for establishing PIMs should be adopted for the treatment of older adults with cancer. There is limited information on polypharmacy in Asian older adults with metastatic cancer, especially for those undergoing palliative chemotherapy. This article reports on the prevalence of polypharmacy, potentially inappropriate medication use, and potential drug‐drug interactions in older patients with cancer in Korea.