The aim of this study was to investigate the association between frailty and polypharmacy using three different frailty screening tools. This was a cross-sectional study of people aged ≥65 years. Participants were included and interviewed using questionnaires. Polypharmacy was defined as the daily use of eight or more pills. Frailty was assessed using a screening tool, including (1) the Fatigue, Resistance, Ambulation, Illness and Loss of Weight Index (5-item FRAIL scale), (2) the Cardiovascular Health Phenotypic Classification of Frailty (CHS_PCF) index (Fried’s Frailty Phenotype), and (3) the Study of Osteoporotic Fracture (SOF) scale. A total of 205 participants (mean age: 71.1 years; 53.7% female) fulfilled our inclusion criteria. The proportion of patients with polypharmacy was 14.1%. After adjustments were made for comorbidity or potential confounders, polypharmacy was associated with frailty on the 5-item FRAIL scale (adjusted odds ratio [aOR]: 9.12; 95% confidence interval [CI]: 3.6–23.16), CHS_PCF index (aOR: 8.98; 95% CI: 2.51–32.11), and SOF scale (aOR: 6.10; 95% CI: 1.47–25.3). Polypharmacy was associated with frailty using three frailty screening tools. Future research is required to further enhance our understanding of the risk of frailty among older adults.