IntroductionPolypharmacy, the use of multiple medications, is a growing concern among middle-aged and older patients, posing potential risks and challenges in healthcare management.AimThis study aimed to identify the prevalence of polypharmacy and hyper-polypharmacy among populations of middle-aged vs. older patients and identify its associated common comorbidities and prescribed medications in Qatif Central Hospital (QCH), Saudi Arabia.MethodsPatients aged 40 years or older who presented to an outpatient medical care clinic at QCH, Saudi Arabia, between 1 January and 31 December 2021 were included, and their comorbidities, prescribed medications, and recent clinical laboratory test results were collected. The Charlson comorbidity index (CCI) score was calculated to predict the risk of mortality. Logistic regression was used to compute the association between the prevalence of polypharmacy and patient characteristics. The results were presented as odds ratios (ORs) and 95% confidence intervals (95% CIs).ResultsA total of 14,081 patients were included; 31% of the cohort comprised older patients, and 66% of the cohort was identified with polypharmacy. The majority of the polymedicated patients were presented to an internal medicine care unit (34%). The prevalence of polypharmacy was positively associated with CCI (OR = 3.4, 95% CI 3.3–3.6), having a disease related to the musculoskeletal system (MSD) (OR = 4.2, 95% CI 3.8–4.7), and alimentary tract and metabolism (ATM) (OR = 3.8, 95% CI 3.4–4.2). Conversely, the prevalence of polypharmacy was negatively associated with age (OR = 0.9, 95% CI 0.89–0.91) and patients with cardiovascular diseases (OR = 0.6, 95% CI 0.5–0.7).ConclusionPolypharmacy is still an ongoing concern. Patients, particularly those with diseases related to MSD or ATM, should be considered for reviewing prescriptions by pharmacists to reduce the risk of adverse drug reactions and future consequences of polypharmacy.