Background: Handgrip strength (HGS) is a widely used indicator of muscle strength and physical performance, and its recovery in rehabilitation reflects functional improvement. Although polypharmacy is common among older patients and associated with functional decline, its impact on muscle strength recovery during convalescent rehabilitation remains unclear. We investigated the association between polypharmacy and in-hospital HGS recovery and its modification by cognitive function. Methods: This retrospective observational study included patients aged ≥65 years admitted to a convalescent rehabilitation hospital between April 2017 and March 2024. Polypharmacy was defined as using six or more regular prescription medications at discharge. HGS recovery was calculated as the logarithmic ratio of discharge to admission HGS. Multivariate linear regression analyses were performed with stratification by cognitive status, and multivariate logistic regression analysis examined the association between polypharmacy and medications associated with muscle weakness. Results: Among 1,650 patients analyzed, 1,350 had low HGS and 300 had normal HGS at admission. In the low-HGS group, polypharmacy was independently associated with poorer HGS recovery (B=-0.064), corresponding to approximately 6% lower improvement. Stratified analyses showed that the association was significant in patients with cognitive impairment but not in patients without cognitive impairment. No significant association was found in patients with normal HGS. Polypharmacy was strongly associated with use of medications known to adversely affect muscle function. Conclusion Polypharmacy was associated with poorer HGS only in patients with low baseline HGS, and stratified analyses suggested a stronger association in those with cognitive impairment.