Aim: Polypharmacy (PP) is a common problem among the older adults and has a potential effect on health-related problems. However, the significance of PP in older advanced non–small cell lung cancer (NSCLC) patients and those on oral molecular-targeted anticancer agents is unclear. Methods: This retrospective study reviewed the records of 334 advanced NSCLC patients who underwent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. PP was defined as >=5 concomitant medications. Potentially inappropriate medication (PIM) use was measured using the updated screening tool of older people’s prescriptions (STOPP) ver. 2 criteria. We also estimated survival distributions using the Kaplan–Meier method, compared between–group differences using the log-rank test, explored potential predictors of survival using Cox regression, and performed cluster analysis to identify factors affecting multiple-medication use. Results: The PP and PIM use prevalence was 38.4% and 31.9%, respectively. The median overall survival (OS) for PP(+) and PP(–) patients was 19.4 months (95% CI = 14.1–24.8) and 27.3 months (95% CI = 22.6–36.4), respectively (P < 0.001). Multivariate analysis revealed a significant correlation between PP and OS. The frequency of unexpected hospitalization during EGFR-TKI treatment was higher in PP(+) compared to PP(–) patients (49.4% vs. 29.4%; P = 0.0032; OR = 2.34; 95% CI = 1.31–4.23). Conclusion: PP is an independent prognostic factor in older NSCLC patients taking EGFR-TKIs. PP can be used as a simple indicator of such patients’ comorbidities and symptoms or as a predictive marker of unexpected hospitalization during treatment.