Background:The most prevalent form of kidney failure is diabetic nephropathy (DN) and subsequent mortality and morbidity. L carnitine (L.C) and fenofibrate have been formerly showed to be potent in treating DN in rats. Objective: The current work compares the effectiveness of L.C and/or fenofibrate in streptozotocin (STZ)-induced DN and the mechanism that leads to it. Materials and Methods: Thirty male Sprague Dawley rats were subdivided into five groups; Control group, Diabetic (D) group, D/fenofibrate group, D/ L.C group, D/combination (fenofibrate/L.C) group. Streptozotocin as a single dose was used to cause DN in rats by intraperitoneal injection. Results: Serum creatinine (SCr) and blood urea nitrogen (BUN) levels were significantly higher in DN rats, although overall antioxidant capacity was significantly lower (TAC). Histopathological tests of the kidney confirmed these biochemical findings on the same axis. Treatment with L.C and/or fenofibrate, on the other hand, clearly strengthened these functional parameters, TAC, and diabetic histological shifts. The transforming growth factor-1 (TGF- β1)/SMAD pathway was used to investigate the potential mechanism of L.C and/or fenofibrate on diabetic kidney injury defense. The findings revealed that diabetic rats treated with L.C and/or fenofibrate had their TGF- β1/SMAD pathway rebalanced. Surprisingly, taking L.C and fenofibrate at the same time had better safety than any medication alone. Conclusion: Experiments revealed that L.C and/or fenofibrate can be a powerful agent for stopping the development of DN through inhibiting TGF-β1/SMAD -mediated renal fibrosis, whilst their combination exerted a superior renoprotective effect.