There is a significant increase noted in the incidence and prevalence of Type 2 diabetes mellitus (T2DM). The global number of diabetic patients is projected by the International Diabetes Federation (IDF) to reach 552 million. T2DM disease has chronic and progressive nature. More than fifty percent of patients do not attain adequate glycemic control despite initial sufficient monotherapy. To maintain target glycated hemoglobin (HbA1c) levels (<7%), dose adjustment and adoption of several diabetes therapies become necessary in many cases. Compared to monotherapy, a fixed drug combination of oral agents and metformin has proven to be more efficacious to maintain levels of blood glucose and HbA1c. The combination of dipeptidyl peptidase-4 inhibitors (DDPIs) and metformin has been explicated to effectively decrease HbA1c to a relatively higher degree compared to the use of either agent individually. This combination addresses various pathophysiological processes involved in T2DM pathogenesis. Additionally, the concerned combination is safe and associated with a lower risk of hypoglycemia. Moreover, it is well-tolerated and prescribed as an easy-to-use single pill to improve patient compliance. This review provides an overview of the pharmacology, efficacy, and safety of fixed drug combinations of DDPIs and metformin according to current practice.