Objectives: To evaluate the prevalence of polypharmacy in relation to gender, comorbidity, and age among elderly patients upon discharge from an academic tertiary care hospital in Muscat, Oman. Methods: This cross-sectional study was conducted at Sultan Qaboos University Hospital between February and July 2014. We reviewed the electronic medical records of elderly patients aged ≥ 60 years who were admitted to any of the hospital’s medical wards during the study period and collected data on age, gender, and diagnoses. We also collected information on the medications prescribed on discharge. Polypharmacy was defined as the concurrent use of ≥ 5 medications. Results: A total of 431 elderly inpatients were enrolled, of which approximately 50% were female. Polypharmacy was identified in 76.3% of discharge prescriptions. Gender (adjusted odds ratio (aOR), 1.17; 95% CI 0.73, 1.88, p = 0.502) and age (aOR, 0.98; 95% CI 0.95, 1.00, p = 0.075) had no impact on polypharmacy. On the other hand, a significant association between polypharmacy and comorbidity was observed (aOR, 1.31; 95% CI 1.12, 1.54, p = 0.001). Cardiovascular diagnosis on admission was also identified as being associated with polypharmacy (aOR, 2.66; 95% CI 1.49, 4.75, p = 0.001). More patients had cardiovascular diseases on admission (31.0%), followed by infections (23.0%), and gastrointestinal diseases (13.0%). The most commonly prescribed drugs on discharge were cardiovascular drugs (48.0%), followed by drugs acting on the gastrointestinal system (11.0%), endocrine system (9.2%), and nutrition and blood (7.5%). Conclusions: The prevalence of polypharmacy among elderly medical patients discharged from our hospital was high (76.3%) and was associated with a number of comorbidities and cardiovascular disease as a cause of admission, but not with age or gender. The prevalence of polypharmacy in our institution raises significant concerns over its potential impact on patients’ health outcomes and requires further investigation. Raising physicians’ awareness of health implications of polypharmacy may help reduce the incidence of medication-related adverse events and improve treatment outcomes.