Background <p>The global demographic shift toward an aging population has increased the prevalence of chronic diseases and pharmacotherapy, often leading to polypharmacy and a heightened risk of adverse drug events. The aim of this study was to quantify the prevalence of polypharmacy and characterize patterns of drug use, including potentially inappropriate medications, among older adults residing in Malta’s long-term community care homes.</p> Methods <p>A multicenter, cross-sectional observational study was conducted across four state-run care homes in Malta. Data were collected from the medical records of consenting residents, covering demographics, multimorbidities, functional dependency, and drug use. Inappropriate use of medications and drug–drug interactions were identified using the STOPP/START criteria and the EPOCRATES Online Web Checker.</p> Results <p>Nearly all participants (93.7%) were exposed to polypharmacy, with 19.7% of the 1969 prescriptions analyzed meeting the criteria for inappropriate medication use. The most frequent potentially inappropriate medications included the prolonged use of proton pump inhibitors (47.6%), loop diuretics (40.3%), and antipsychotics (30.4%). Notable therapeutic gaps included the suboptimal anticoagulation rates in residents with atrial fibrillation and the absence of regular bronchodilator use among residents with chronic obstructive pulmonary disease. Potential risk for orthostatic hypotension was the most common drug interaction, affecting 63.4% of participants.</p> Conclusion <p>While the frequency of potentially inappropriate medications was comparatively low, the widespread prevalence of polypharmacy, antipsychotic administration, and essential treatment gaps necessitates immediate clinical intervention. Standardizing the use of STOPP/START criteria and implementing regular multidisciplinary medication reviews are essential to enhance safety and therapeutic outcomes.</p>