Background <p>Type 2 diabetes mellitus (T2DM) is the most common type of endocrine disorder among adults, accounting for 90%-95% of diabetes mellitus globally. In Uganda, non-adherence to anti-diabetic medication remains high at 38.1%. This results in complications like diabetic ketoacidosis, hyperglycemia and microvascular complications.</p> Objective <p>To determine the prevalence of adherence to anti-diabetic medication, its associated factors, and to explore barriers, facilitators, and strategies for improving adherence among adults with T2DM attending the diabetic clinic at Soroti Regional Referral Hospital (SRRH).</p> Methods <p>An explanatory sequential mixed-methods design was employed, consisting of a cross-sectional quantitative study followed by a descriptive qualitative study. The quantitative component involved systematic random sampling of 376 adults aged ≥ 18 years with T2DM, while the qualitative component purposively recruited 15 adults with T2DM. Quantitative data were collected using a structured interviewer-administered questionnaire and analyzed using SPSS version 27, while qualitative data were collected using an in-depth interview guide and analyzed using Open Code version 4.03. The prevalence of adherence measured as proportion of patients who were fully adherent to their prescribed anti-diabetic medication regimen and expressed as a percentage. Modified Poisson regression was used to determine factors associated with adherence, reporting adjusted prevalence ratios (aPRs). Inductive thematic analysis was used to generate themes and subthemes from qualitative data.</p> Results <p>The prevalence of adherence to anti-diabetic medication was 51.3% (95% CI: 46.0%–56.0%). Factors significantly associated with adherence included female sex (aPR = 2.215, p &lt; 0.001), having family support (aPR = 2.972, p &lt; 0.001), ever receiving health education (aPR = 2.522, p &lt; 0.001), and consistent availability of anti-diabetic medication at the hospital pharmacy (aPR = 2.194, p = 0.029). Qualitative findings generated three major themes: medication- and health-system–related barriers (financial constraints, drug stock-outs, side effects), patient- and social-related facilitators (family support, health education, regular follow-up), and recommended strategies for improvement (strengthening community support, improving drug supply, and enhancing patient–provider communication).</p> Conclusion <p>Adherence to anti-diabetic medication among adults with T2DM at SRRH is suboptimal. Key determinants include female sex, family support, health education, and reliable medication supply. To improve adherence, the study recommends routine adherence assessment, structured health education, consistent medication availability, family engagement, and integration of adherence counseling into professional development. Community-based health education, mobile health reminders, and family-centered counseling programs are promising interventions that should be further explored to enhance adherence and reduce diabetes-related complications.</p>