Background: The prevalence of diabetes has been increasing exponentially both in developing and developed nations. Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) across the world. Aim of the study: this work aimed to explore the potential efficacy of ranolazine, ivabradine and trimetazidine in prevention of development and progression of experimentally induced diabetic nephropathy in nicotinamide- streptozotocin (NA-STZ) type 2 diabetic rats’ model. Materials and Methods: 30 Rats were divided into: (Group I) normal control group, (Group II) non treated diabetic group received no treatment, (group III) ranolazine treated diabetic group received ranolazine (20 mg/kg twice daily), (Group IV) ivabradine treated diabetic group received ivabradine (10 mg/kg/day) and (Group V) trimetazidine treated diabetic group received trimetazidine (10 mg/kg/day). Results: ranolazine, ivabradine and trimetazidine induced significant decrease in fasting blood glucose, renal function parameters, renal MDA and renal iNOS in renal homogenate. Serum inflammatory marker (RBP) also significantly decreased together with genes of vascular damage (ET-1), significant down regulation of m RNA in Caspase-3 level and TGFB-1 was downregulated compared with diabetic non treated rats. Conclusion: Current findings confirmed ameliorative impact of ivabradine, trimetazidine and ranolazine on DN induced by NA-STZ T2DM. Ivabradine showed the best effect followed by trimetazidine. Ranolazine treated group had the lowest prophylactic effect.