Introduction: Diabetes mellitus is a complex chronic metabolic condition defined by persistent hyperglycemia caused by abnormalities in insulin activity and/or secretion. Metformin, the mainstay of diabetic treatment, is frequently made more successful when combined with additional medications like glimepiride or vildagliptin. The current study aimed to compare the efficacy and safety of vildagliptin-metformin combination to glimepiride-metformin combination. Materials and Methods: The study was a three-month prospective randomized comparative study. This study included 60 patients who met the inclusion criteria and were divided evenly into two groups: Group A (metformin-glimepiride) and Group B (metformin-vildagliptin). Efficacy indicators such as fasting blood glucose, 2-hour postprandial glucose, and HbA1c were measured, and any side effects observed during the study were noted. Results: The majority of patients in both groups are aged 61 to 70 years. Of the 60 cases, 29 were men and 31 were women. Before starting treatment, the average FBS levels in Groups A and B were 162.13±18.21 mg/dl and 168.24±19.23 mg/dl, respectively. Finally, there was a significant difference in the decrease in FBS levels between the two groups. Before starting therapy, Groups A and B had average PPBS levels of 228.34±23.45 mg/dl and 232.42±24.32 mg/dl, respectively. Finally, the two groups differed significantly in their ability to reduce PPBS levels. Before starting medication, the average hemoglobin A1C levels in Groups A and B were 8.43±1.24 mg/dl and 8.48±0.81 mg/dl, respectively. Finally, there was a substantial difference between the two groups in terms of Hemoglobin A1C level reduction. Hypoglycemia occurred in 37% of Group A patients and 3% of Group B patients, while 10% of Group A patients gained weight. Conclusion: The combination of vildagliptin and metformin exhibited higher efficacy than the combination of glimepiride and metformin, as well as a better side effect profile with decreased risks of hypoglycemia and weight gain.