Background: Diabetes mellitus is a heterogeneous chronic metabolic disorder principally characterized by persistent hyperglycemia resulting from defects in insulin action and/or insulin secretion. In course of time, prolonged hyperglycemia and associated metabolic aberrations result in tissue toxicity manifested as accelerated atherosclerosis, renoretinal microangiopathy, and neuropathy leading to a variety of vascular, neurological, and focal complications. Aim and Objective: The aim of this study is to evaluate the efficacy and safety of metformin and vildagliptin versus metformin and glimepiride in patients with Type 2 diabetes mellitus. Materials and Methods: This is a longitudinal interventional study. A total of 60 patients were enrolled in the study. Those patients who were already on metformin 500 mg bid with poor glycemic control were included in the study. These 60 patients were divided into two groups each consisting of 30 patients. Group A patients received glimepiride 1 mg bid and metformin 500 mg bid. Group B patients received vildagliptin 50 mg bid and metformin 500 mg bid. The total period of the study was 3 months. Results: After 3 months of treatment, both the groups caused a significant decline in blood glucose levels both fasting blood sugar (FBS) as well as postprandial blood sugar (PPBS) levels. There was a significant difference between the two groups in reducing the FBS levels and PPBS. Hemoglobin A 1c (HbA1c) was also reduced significantly in both groups at 12 weeks. After 3 months of therapy, there was a reduction in HbA 1C in B group. The reduction of HbA 1C was not statistically significant between the two groups. Adverse effects were more with metformin and glimepiride group at the end of 3 months therapy. There was a significant difference in the incidence of adverse effects between both the groups. Conclusions: Vildagliptin and metformin combination provided better efficacy comparable to that of glimepiride and metformin combination and resulted in better adverse effect profile with lower risks of hypoglycemia and weight gain.