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The present study was performed to investigate the underlying defensive mechanisms of formononetin in nephrotoxicity by using in vivo and in vitro models. MTT assay was carried out to test the toxic effect of formononetin in HEK-293 cells which were treated with formononetin (5, 10, 20 µM) and cisplatin (20 µM). The concentrations of TNF-α and nitric oxide (NO) were determined in the cell supernatant. Nephrotoxicity in rats was induced by a single intraperitoneal injection of cisplatin at a dose of 5 mg/kg, and formononetin at doses of 10 and 30 mg/kg was used to study protective activity. Blood urea nitrogen (BUN), serum creatinine, oxidative strain, a proinflammatory cytokine, NO, and histological alteration were measured to find the therapeutic activity of formononetin. Cells treated with cisplatin showed increased levels of TNF-α and NO. Formononetin-treated cell lines showed a decreased level of TNF-α and NO production. In vivo studies determine that in the disease control group, the levels of proinflammatory cytokines, oxidative stress, BUN, and creatinine were increased because of cisplatin-induced nephrotoxicity. After the treatment of formononetin for 14 days, the levels of cytokines and oxidative stress were reduced in the test control group as compared to the disease control group. The inhibitory action of formononetin on inflammatory responses was achieved by reducing the expressions of cytokines. Cisplatin-treated rats showed the altered structure of kidney tissue; meanwhile, formononetin normalizes the structure of kidney tissue. From our findings, we conclude that formononetin has therapeutic potential in renal complications like nephrotoxicity, by inhibiting the production of proinflammatory cytokines (i.e., TNF-α) and oxidative stress (i.e., NO) in HEK-293 cell lines as well as protecting the rats from nephrotoxicity. [ABSTRACT FROM AUTHOR]