Background and purpose Elderly patients exposed to drugs with anticholinergic or sedative properties may have an increased risk of adverse events. This study aimed to assess the relationship between patient characteristics and changes of exposure to anticholinergic and sedative medications during their hospital stay. Methods A multicentre longitudinal study was set up on hospitalized patients (aged ≥65 years) using at least one drug at admission. The primary outcome was change of exposure to anticholinergic and sedative drugs between admission and discharge. Sociodemographic characteristics of the patients, comorbidities, life habits and information about the hospital stay (origin of admission, reasons for hospitalization) were collected. Results The study included 337 patients (mean age, 85.4 years) with an average hospital stay of 30.1 ± 37.5 days. The drug burden index increased during the hospital stay among males ( P = 0.03), patients for whom the reason for hospitalization was either a stroke ( P = 0.001) or inability to stay in their own home ( P = 0.001), and patients with diabetes mellitus ( P = 0.009). In the adjusted model, drug burden index increased among patients hospitalized for stroke, inability to stay in their own home or post‐surgery, and for patients with diabetes mellitus or hypertension. Conclusions The drug management of elderly patients during hospital stays may increase exposure to anticholinergic and sedative drugs. Although the anticholinergic and sedative properties may be in relation to the therapeutic purpose, they also represent an unexpected risk. Physicians and clinical pharmacists should consider performing optimization of the drug prescriptions for patients at risk.