Background: Type 2 diabetes mellitus (T2DM) is a major public health concern in Nigeria, with oral antidiabetic drugs (OADs) forming the mainstay of treatment. This mixed-methods study compared the efficacy and side effect profiles of OAD classes among T2DM outpatients at Rivers State University Teaching Hospital (RSUTH). Methods: A retrospective analysis of 400 patient records (January 2023–December 2024) examined prescribing patterns, glycemic control (HbA1c, fasting blood glucose [FBG]), and adherence (Medication Possession Ratio). A prospective cohort (N = 450, January–June 2025) assessed outcomes via interviews and lab tests. Data were analyzed using χ² tests, Pearson correlations, and ANOVA in SPSS v27 and GraphPad Prism 10.2 (p ≤ .05). Power analysis indicated 80% power for detecting medium effects (f = 0.25). Results: Baseline HbA1c was 12.59% ± 3.40%, reducing to 10.87% ± 3.08% at follow-up (p = .001), with 42% achieving <7%. Sulfonylureas and SGLT2 inhibitors showed trends toward greater reductions (0.9%–1.1%), but differences were non-significant across classes (p > .05). Common side effects included hypoglycemia (44%–77% with sulfonylureas) and gastrointestinal upset (9%–40% with metformin/DPP-4 inhibitors); no significant adherence correlations (r = –.018 to .064, p = .202–.877). Females had poorer adherence (χ² = 7.829, p = .019). Conclusion: OADs provided modest glycemic improvements, but suboptimal control persists. Side effects were mild and did not strongly impact adherence. Tailored therapy and adherence support are recommended, with newer agents showing promise if accessible.