Background <p>Sarcopenia and polypharmacy are common geriatric syndromes associated with adverse outcomes in older adults. Although previous studies have suggested a potential relationship between these conditions, the independent nature of this association remains unclear, particularly among hospitalized populations. Certain medication classes may also exert muscle-protective effects that could influence this relationship.</p> Purpose <p>To examine whether polypharmacy is independently associated with sarcopenia in hospitalized older adults and to evaluate the relationship between specific medication classes and sarcopenia prevalence.</p> Methods <p>This cross-sectional study included hospitalized patients aged ≥ 65 years. Sarcopenia was diagnosed according to EWGSOP2 criteria, skeletal muscle mass was assessed using bioelectrical impedance analysis (BIA), and polypharmacy was defined as the regular use of five or more medications. Medication classes with possible muscle-protective effects were identified through a targeted literature review. Multivariate logistic regression analysis was performed to assess independent associations.</p> Results <p>A total of 206 patients were included (60% female; median age: 78 years). The prevalence of sarcopenia was 39.8%. Polypharmacy was common in both sarcopenic (87.8%) and non-sarcopenic (80.6%) patients (<i>p</i> = 0.33), and the number of medications did not differ significantly between groups (7 ± 3 vs. 7.87 ± 3; <i>p</i> = 0.15). Angiotensin receptor blocker (ARB) use was more frequent in the non-sarcopenic group (40% vs. 15%; <i>p</i> = 0.005). In multivariate analysis, ARB use remained independently associated with lower odds of sarcopenia.</p> Conclusion <p>Polypharmacy was not independently associated with sarcopenia in hospitalized older adults. However, ARB use was significantly associated with lower likelihood of sarcopenia, suggesting a potential muscle-protective effect. Further longitudinal research is warranted to clarify causality.</p>