BACKGROUND: The pathophysiology and severity of kidney impairment due to doxorubicin (DOX) treatment are markedly influenced by oxidative stress and inflammation. Naringin (NG), a natural flavonoid, has anti-inflammatory and antioxidant properties. The nephroprotective effect of NG on DOX-induced kidney toxicity was investigated to increase its utility in clinical settings. METHODS: DOX toxicity was induced by a single ip injection (15 mg/kg) and for possible protection NG (100 mg/Kg) was used. RESULTS: Kidney damage and dysfunction were indicated by an elevation in the levels of creatinine, urea, uric acid, and the activity of ALP and LDH in serum, KIM-1, and NAGAL in kidney, and a significant decrease in nephrin and podocin in renal tissue. These disrupted glomerular and tubular function indicators were remarkably ameliorated by oral administration of NG (100 mg/kg) daily for 10 days before DOX treatment and continued for an additional four days post-Dox treatment. The nephroprotective effect of NG was confirmed by the improvement of histopathological and PAS histochemical investigations. The mitigating impact of NG was verified by normalization of the redox balance, evidenced by a significant amelioration of ROS levels, oxidative stress markers (MDA, PC, 8-OHdG), and antioxidants (GSH, GPx, GR), as well as upregulation of Nrf2 expression in kidney. Furthermore, NG significantly prevented the increase in the inflammatory mediators (IL-6, IL-1β, TNF-α, and NF-κB) and upregulated the anti-inflammatory IL-10 in DOX-treated rats. The expression of TGF-β1 and the apoptotic protein caspase-3 in the kidneys significantly decreased as a result of the improvement in redox state in renal tissue. Additionally, NG demonstrated anticancer effects and their combination showed synergistic anticancer impact on larynx and colon cancer cell lines in vitro study. CONCLUSIONS: NG demonstrated remarkable protection of kidney against DOX treatment.