Background: Older adults often have chronic diseases for which they receive multiple drugs, which may be potentially inappropriate. Objectives: We aimed to describe the potentially inappropriate medications (PIMs) leading to adverse drug events (ADEs) in older patients with cancer. Our secondary objectives were to evaluate the association of nutrition, cognition, and frailty with PIM-related ADEs and to assess the impact of PIM-related ADEs on overall survival (OS). We also investigated the cut-off for defining polypharmacy as related to ADEs. Materials and Methods: This was a retrospective observational study on patients with cancer aged 60 years and over who were assessed in the geriatric oncology clinic at the Tata Memorial Hospital (Mumbai, India) from June 2018 to August 2022. Medications, PIM assessment, nutrition (assessed by Mini Nutritional Assessment [MNA]), cognition (assessed by Mini Mental State Examination [MMSE] and Hindi Mental State Examination), and frailty (assessed by the Clinical Frailty Scale [CFS]) were extracted from the geriatric oncology clinic database. PIMs were identified using the Beers criteria, European Union-7 (EU[7])-PIM, Screening Tool of Older person’s Prescriptions/Screening tool to Alert to Right Treatment (STOPP/START), Fit fOR The Aged (FORTA), and PRISCUS list. Results: In total, 1472 patients were assessed in the geriatric oncology clinic, of which 823 (55.9%) were enrolled in the study. There were 1287 PIMs detected in 823 patients, of which 431 (33.5%) led to ADEs and 856 (66.5%) did not. Proton pump inhibitors and tramadol were the most common PIMs identified. ADEs were noted in 54 (14.7%) patients on proton pump inhibitors and in 145 (61.1%) patients on tramadol. ADEs were significantly associated with malnutrition, lower cognition, and frailty. The median MNA score in patients without and with ADEs was 20.5 (interquartile range [IQR], 17.5-24.0) and 19.5 (IQR, 15.5–23.5), respectively; P, 0.001. The median MMSE score for the patients without and with ADEs was 28 (IQR, 26-29) and 27 (IQR: 25-29), respectively; P, 0.001. The median CFS scores for the patients without and with ADEs were 3 (IQR, 2-4) and 4 (IQR, 3-5), respectively; P < 0.001. The median OS in patients without and with ADEs was 13.1 months (95% confidence interval [CI], 10.64-17.87) and 10.2 months (95% CI, 8.80-12.85), respectively; P, 0.002. The optimal cut-off for polypharmacy leading to ADEs was 4.5 medications. Conclusions: There is a dire need to recognize and appropriately manage PIMs in older patients with cancer as PIM-related toxicities may negatively impact survival. Monitoring PIMs and following the recommendations to optimize the dose, avoid the drug, and find alternatives may improve the oncologic outcomes. Future studies should focus on adding a control group of patients not on PIMs, following up on PIM after recommendations, and investigating the impact of these recommendations on oncologic outcomes (Clinical Trials Registry-India: CTRI/2020/04/024675).