Nephrotoxicity is the most relevant side effect of widely used antineoplastic drug cisplatin. Therefore use of cisplatin is limited with about 25–35% of patients experiencing a significant reduction in renal function after a single dose of cisplatin. Cisplatin-induced nephrotoxicity is related to an increase in oxidative stress in the kidney. In the present study, we investigated biochemically, histopathologically and at the molecular level how the melatonin display antioxidant effect against cisplatin-induced nephrotoxicity. The present study demonstrates that the administration of melatonin exerts a renal protective effect in a rat model of nephrotoxicity provoked by a single intraperitoneal (i.p.) injection of cisplatin. In the animals that receive melatonin, the levels of serum urea and creatinine indicating reduced renal injury were significantly lower as compared to the cisplatin injected group. The renal tissue MDA and 8-iso-PGF2α levels showed a significant increase in sisplatin-treated rats compared the control rats. SIRT–1 protein expression levels were significantly up-regulated while NAMPT, COX-2, TGF-β1 and TNF-α protein expression level were down-regulated in rats treated with melatonin. Histopathological findings showed that melatonin pretreatment decreased the cisplatin-induced tubular necrosis and most of the changes produced by cisplatin. Taken together, results of this study indicate that melatonin attenuates cisplatin-induced nephrotoxicity by modulating NAMPT/SIRT-1 signaling, and reducing the inflammation by inhibiting COX-2, TGF-β1 and TNF-α.