Background: The cisplatin is one of the widely employed platinum-based drugs as the chemotherapeutic substance for the treatment of various cancers such as bladder cancer, prostate cancer, cervix cancer, and lung cancer. Hence, the present work was designed to test the curative efficacy of phloretin against the cisplatin-induced nephrotoxicity in rat model. Materials and Methods: Male Wistar albino rats were divided into five groups and the Group I rats were served as control, Group II rats were injected with cisplatin (8 mg/kg), Group III rats were administered with the low dose of phloretin (25 mg/kg), Group IV rats were administered with the high dose of phloretin (50 mg/kg), and the Group V rats were administered with the standard drug silymarin (50 mg/kg) for 10 days. After the experimental period, the animals have been sacrificed and collected all the samples for further analysis. Results: In the current study, the cisplatin was exhibited the severe renal damage in Wistar albino rats by possessing the various clinical complications such as increased serum urea, proteinuria and creatinine levels, decreased antioxidant enzymes level, increased DNA fragmentation, elevated oxidative stress, and severe injury to renal tissues. In addition, the cisplatin increased the poly (ADP-ribose) polymerase-1 and caspase-3 activity and pro-inflammatory cytokines level such as tumor necrosis factor alpha and interleukin-1 β. Whereas, the treatment with the low dose and high dose of phloretin (25–50 mg/kg) was exhibited a significant (P < 0.05) attenuation against the cisplatin-induced nephrotoxicity in experimental rats. Conclusion: The phloretin treatment significantly protected the kidneys against cisplatin-induced renal damages in rats.