Background and Aim: Cisplatin (Cis) is a very effective anticancer medication. The application of Cis is restricted due to its significant adverse effects. Hence, we conducted this work to examine the underlying mechanism by which ROF and Mel protect against Cis-induced kidney injury. Materials and Methods: Fifty male Sprague-Dawley rats were divided into five groups. Control group: Animals were given a 0.9% saline solution. Experimental group: The rats were administered a single dosage of 6 mg/kg. ROF group: The rats were administered a dose of 1.2 mg/kg. The Mel group was administered a dose of 10 mg/kg/day. The ROF + Mel group had a Cis injection before being delivered. Results: Concentrations of blood creatinine, BUN, and total protein were higher in the Cis group compared to the control group. The joint effect of ROF and Mel substantially reduced values of blood creatinine, BUN at the 5-day and 11-day marks (p < 0.05). Cis increased MDA levels and inhibiting the functions of SOD, GSH, and CAT. The influence of ROF and Mel on these effects was observed after 11 days. The simultaneous administration of ROF and Mel led to a notable upregulation of Nrf2 and HO-1 expression compared to the Cis group after 11 days (P < 0.05). Conclusion: The study shown that the kidneys can be preserved against Cis-induced injury by combining cisplatin-based medications with ROF and Mel antioxidant-based therapy interventions.