Background: Medication adherence and health-related quality of life (HRQoL) serve as key determinants of therapeutic success in type 2 diabetes mellitus (T2DM). While sodium–glucose cotransporter-2 (SGLT-2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors continue to be widely recommended as add-on therapies, comparative real-world evidence on adherence and QoL outcomes remains limited. Objective: To evaluate and compare medication adherence and QoL in T2DM patients receiving SGLT-2 inhibitors versus DPP-4 inhibitors administered as adjunct therapies. Methods: A prospective, observational cohort study was undertaken for a period of 12 months at a tertiary hospital and affiliated clinics. In total, 200 individuals with T2DM (100 per group) were followed after initiating either SGLT-2 inhibitors (empagliflozin/dapagliflozin) or DPP-4 inhibitors (sitagliptin/linagliptin). Medication adherence assessment was conducted by means of 8-item Morisky Medication Adherence Scale (MMAS-8) and pill counts, whereas HRQoL underwent evaluation with the Diabetes-39 (D-39) questionnaire at baseline, 6 months, and 12 months. Statistical analyses involved repeated measures ANOVA and logistic regression. Results: Both groups demonstrated significant improvements in adherence and QoL from baseline (p < 0.001). Adherence scores increased from 5.0 ± 0.82 to 8.0 ± 0.82 in the SGLT-2 group and from 6.0 ± 0.82 to 9.67 ± 0.47 in the DPP-4 group, with consistently higher adherence in the DPP-4 cohort (p < 0.001). QoL improved more markedly in the SGLT-2 group (5.5 ± 1.51 to 7.96 ± 1.04; Δ = +2.46) compared to the DPP-4 group (4.95 ± 0.81 to 6.35 ± 0.48; Δ = +1.4; p < 0.001). Conclusion: Significant enhancements in adherence and QoL were observed with SGLT-2 and DPP-4 inhibitors in T2DM patients. DPP-4 inhibitors were associated with superior adherence, while SGLT-2 inhibitors conferred greater QoL improvements. These findings underscore the importance of tailoring therapy to optimize both clinical and patient-reported outcomes in long-term diabetes management.