Background <p>Medication suboptimization leads to poor clinical outcomes, increased healthcare costs, prolongation of hospital stay, decreased quality of life, morbidity, and mortality among Patients with Comorbid Type 2 Diabetes and Hypertension.</p> Objective <p>To identify determinants of medication suboptimization among patients with comorbid type 2 diabetes and hypertension in a tertiary hospital, Southwest Oromia, Ethiopia.</p> Methods <p>A prospective observational study was conducted. Data were collected through medical records (medication, medical condition, and laboratory tests), patient interviews, and an observational method. Descriptive statistics were presented as frequencies, percentages, and means ± standard deviation. Bivariate and multivariate logistic regression were used to determine the determinants of medication suboptimization. In multivariate logistic regression, variables were considered statistically significant at a <i>p</i>-value &lt; 0.05.</p> Result <p>A total of 168 type 2 diabetes patients with hypertensive patients were studied. More than half of the participants, 93 (55.4%), were males. The prevalence of medication suboptimization was 79.2%. Needs for additional drug therapy (57.4%) and non-adherence (35.5%) were the most common observed medication suboptimizations. The determinants of medication suboptimization were patients having history of alcohol drinking (AOR = 6.013, 95%CI; 1.013–35.682), uncontrolled hypertension (AOR = 10.608, 95%CI; 3.173–35.465), poorly controlled type 2 diabetes mellitus (AOR = 3.268, 95% CI;1.033–10.334) and secondary education level (AOR = 0.056, 95% CI; 0.005–0.669).</p> Conclusion <p>The present study revealed that secondary educational level was protective, while a history of alcohol drinking, uncontrolled hypertension, and uncontrolled diabetes mellitus were determinants of medication suboptimization.</p>