Polypharmacy, often defined as the concurrent use of five or more medications, has become increasingly common due to various factors, including shifts in lifestyle and a rise in health-related issues among individuals. However, using multiple medications could bring more issues to the patient, as it is linked to poor health outcomes, including medication nonadherence, adverse pharmacological effects, and decreased quality of life (QoL). This study aimed to determine the prevalence of polypharmacy and identify drug-related problems among adult patients in Al-Ahsa. A cross-sectional study was conducted among adult patients living in Al-Ahsa, Saudi Arabia, taking five or more medications. A self-administered questionnaire was distributed among the target population using an online survey. The questionnaire included sociodemographic data (i.e., age, sex, education, etc.), a questionnaire to assess behaviors regarding the use of polypharmacy, and a 10-item questionnaire to measure medication-related quality of life (MRQoL). In total, 196 of the 1,088 patients surveyed took five or more medications, indicating an 18% prevalence of polypharmacy. Among the 196 patients, 26.5% reported poor medication-related QoL. In univariate analysis, sex, occupational status, average monthly income, hypertension, asthma, difficulty managing medications, and side effects experienced were significantly associated with MRQoL. Independent significant predictors of poor MRQoL were having asthma and difficulty managing medications. The prevalence of poor medication-related quality of life among adult patients in our region was 26.5%, lower than that in previous studies. Poor MRQoL was associated with lower monthly income, hypertension, asthma, side effects, and difficulty managing medications.