Neuropathic pain is a common disorder characterized by negative and positive subjective signs and symptoms ranging from numbness to crippling pain. Type 2 diabetes mellitus (T2DM) is the primary cause of neuropathy and neuropathic pain. Diabetic neuropathic pain (DPN) is one of the most common diabetes mellitus complications. The study was aimed to analyze the efficacy and safety of Pregabalin, Duloxetine, and their combination with Epalrestat in T2DM neuropathic patients. The study was conducted on 200 subjects. The patients were divided into 4 groups each comprising of 50 patients. Group I(P) was subjected to Pregabalin (150 mg O.D), Group II (D) to Duloxetine (60 mg O.D), Group III (P + E) to Pregabalin + Epalrestat (150 mg + 100 mg (O.D), and Group IV (D + E) to Duloxetine +Epalrestat (60 mg + 100 mg (O.D) and) for a period of 6 months. Various clinical parameters like vibration perception threshold, gycated haemoglobin level, visual analog scale, DPNdiabetic diagnostic questionnaire, advance glycated end products, thiobarbituric acid reactive substances, C-reactive proteins, SF12 score, and cost-effectiveness were assessed at baseline and 3 and 6 months. Results demonstrated that Pregabalin and Epalrestat therapy has a better effect on neuropathic pain reduction than Duloxetine and Epalrestat with strict glycemic control and favorably contributes to the health effective benefits by inhibiting disease progression and fulfills the alternate goals of management of DPN. It has been suggested that Pregabalin and Epalrestat therapy is more efficacious and armamentarium for patients with DPN. It has been suggested that Group III therapy is more efficacious, cost-effective, and armamentarium for patients with DPN.