Background: Despite the use of safe and effective conventional drugs, drug therapy problems (DTPs) pose a threat to the successful management of hypertension. DTPs are of a great concern in health care because of their serious consequences such as poor quality of life, increased health care costs, morbidity and mortality. However, there is no published information regarding the prevalence of DTPs and associated factors among hypertensive patients in Uganda. Objective: The aim of the study was to determine the prevalence and factors associated with DTPs among hypertensive patients at the hypertension clinic of Mbarara Regional Referral Hospital (MRRH). Method: A cross-sectional study was conducted at the hypertension clinic, MRRH, Uganda among 228 hypertensive patients. Data were collected from medical records using a data abstraction tool and patients were interviewed using a structured questionnaire. Data analysis was done using Statistical Package for Social Sciences (SPSS) version 22.0. Descriptive analysis was used to determine the prevalence of DTPs. Logistic regression was used to determine the association between the independent and dependent variables. Variables were considered statistically significant at p-value <0.05. Results: A total of 178 DTPs were identified among 141 hypertensive patients. The prevalence of antihypertensive-related DTPs was 61.8% (95% confidence interval [CI]: 55.3–67.5) with an average of 1.26 ± 0.52 DTPs per patient. Out of 141 participants with DTPs, 109 (77.3%) had one DTP, 27 (19.1%) had 2 DTPs, and 5 (3.5%) had 3 DTPs. The most common types of antihypertensive-related DTPs were ‘dosage too low’ which accounted for 53 (29.8%), followed by ‘adverse drug reactions’ which accounted for 48 (27%). Uncontrolled blood pressure (BP; adjusted odds ratio [AOR]: 4.17; 95% CI: 2.33–7.45, p < 0.001) and routine laboratory test results (AOR: 1.87; 95% CI: 1.04–3.36, p = 0.036) were significantly associated with antihypertensive-related DTPs among hypertensive patients. Conclusion: Almost two-thirds of study participants had antihypertensive-related DTPs. The most common DTPs were ‘dosage too low’ and ‘adverse drug reactions’ which both accounted for almost a third of the total DTPs each. Uncontrolled BP and routine laboratory test results were significantly associated with antihypertensive-related DTPs among the study participants. Our study emphasizes the need for improved patient care by clinical pharmacists to identify and prevent DTPs among hypertensive patients.