This study explored and compared the functional status of polymedicated and non-polymedicated geriatric inpatients at hospital discharge. We used a cross-sectional registry of geriatric patients’ hospital records from a multi-site public hospital center in Switzerland. The analysis included all inpatients aged 65 years old or more admitted between 1 January 2015 and 31 December 2017 (n = 53,690), of whom 67.5% were polymedicated at hospital discharge, 52.1% were women (n = 18,909), and 42.7% were 75–84 years old (n = 15,485). On average, the polymedicated patients’ hospital lengths of stay were six days longer, they presented with more than three comorbidities, and they were prescribed more than nine medications at hospital discharge (p < 0.001). They showed more frequent general mobility decline (43.2% vs. 41.9%), gait disorders (46.2% vs. 43%), fatigue (48.6% vs. 43.4%) and dependence on lower-body care (49.7% vs. 47.6%), and presented a higher malnutrition risk (OR = 1.411; 95%CI 1.263–1.577; p < 0.001). However, the non-polymedicated inpatients had proportionally more physical and cognitive impairments. The comparison of the functional status of polymedicated and non-polymedicated geriatric inpatients at hospital discharge is important for clinicians trying to identify and monitor those who are most vulnerable to functional decline, and to design targeted strategies for the prevention of functional impairment and related adverse health outcomes