Background: Polypharmacy is very common in elderly patients and is associated with detrimental outcomes. Objective: Our objective was to evaluate the associations between a large panel of therapy quality indicators, including explicit lists of potentially inappropriate medications (PIMs; Beers criteria and Screening Tool of Older Persons’ potentially inappropriate Prescriptions [STOPP] criteria), the Anticholinergic Cognitive Burden (ACB) score, and the number of drug–drug interactions (DDIs), with respect to mortality, rehospitalization, and physical function decline within 3 months from hospital discharge in a cohort of hospitalized elderly patients. Methods: We studied 2631 individuals aged ≥ 65 years (median age 79.6; males 48.6%) enrolled in the REPOSI registry. The relationships with mortality and rehospitalization were evaluated using Cox regressions, and relationships with functional status change (as percentage variation of Barthel Index [BI]) were evaluated using mixed linear models. Results: None of the studied indicators was associated with mortality and rehospitalization. Conversely, only ACB was associated with physical function decline, even after correction for confounders (adjusted mean BI variation of − 7.55%; 95% confidence interval [CI] − 12.37 to − 2.47). The number of medications at discharge, particularly polypharmacy (more than five drugs daily), were the only therapy-related factors associated with mortality (adjusted hazard ratio [aHR] 1.05 [95% CI 1.01–1.10] and 1.70 [95% CI 1.12–2.58], respectively) and rehospitalization (aHR 1.05 [95% CI 1.01–1.08] and 1.31 [95% CI 1.01–1.71], respectively). Conclusion: Polypharmacy, a very simple measure, outperformed sophisticated PIM and DDI indicators of quality of therapy as a correlate of primary clinical outcomes, whereas ACB was associated with physical function decline. Thus, innovative approaches to the definition and research of PIMs and DDIs are eagerly awaited from the perspective of averaging the quantitative burden and qualitative interaction of drugs.