Abstract: Background and Objective: Cisplatin-induced nephrotoxicity is a serious complication that restricts its utilization in cancer treatment. Rutin and alpha-lipoic acid have antioxidant effectiveness, anti-inflammatory efficacy and prevent oxidative stress. Therefore, the current study planned to investigate the potential defensive impacts of rutin and alpha-lipoic acid on cisplatin-induced renal damage in rats. Materials and Methods: Fifty-six adult male Wistar albino rats were randomly divided into seven groups. Rats of group 1: Treated with saline as the control. Group 2: Orally received rutin daily for 2 weeks. Group 3: Rats were orally administered with alpha-lipoic acid (ALA) daily for 2 weeks. Group 4: Rats were intraperitoneal (i.p.) injected with cisplatin to develop the acute renal injury. Group 5: Rats injected with cisplatin then treated orally with RT. Group 6: Rats were injected i.p., with cisplatin then treated orally with ALA. Group 7: Rats injected with cisplatin then treated orally with RT and ALA daily for 2 weeks. Results: The cisplatin administration to rats induced nephrotoxicity associated with a significant increase in serum urea, creatinine, albumin and significantly reduce haemoglobin and red blood cells count. The animal treated with cisplatin showed a significant increase in the level of renal malondialdehyde associated with reduction in the levels of glutathione-s-transferase, glutathione reductase and catalase compared to control group. Moreover, cisplatin treated group recorded significant increase in nuclear factor kappa B, IL-6 and p53 levels compared to control group. Additionally, histopathological examination showed that cisplatin-induced interstitial congestion, focal mononuclear cell inflammatory, cell infiltrate and acute tubular injury. In correlation with the cisplatin group, Rutin and alpha-lipoic acid ameliorated cisplatin-induction increase in serum urea, creatinine, albumin, oxidative stress and inflammation were observed. Moreover, rutin and alpha-lipoic acid showed an enhancement in haematological and histopathological structures. Conclusion: These results indicated that rutin and alpha-lipoic acid showed a protective effect against cisplatin-induced nephrotoxicity in rats.