Background: Plant sterols are the major source of micronutrients and have not shown any obvious side effects in human. β-sitosterol is one of the most prevalent phytosterols which have been recorded in ancient medicinal history for its use in the treatment of many chronic diseases,especially cancer. The modulations of mitogen-activated protein kinases' (MAPKs') play a crucial role in the development of human renal cell carcinoma. Objective: The aim of the current study is to evaluate the antigenotoxic and anticancer role of β-sitosterol against renal carcinogen. Materials and Methods: The extent of DNA damage was assessed by the comet assay. The status of p-p38 MAPK,p-c-Jun N-terminal kinase,p-extracellular-signal regulating kinase (ERK),c-fos,c-jun,and endothelial growth factor receptor (EGFR) were analyzed by western blot and polymerase chain reaction techniques. To further confirm the inhibition of ERK-2 by β-sitosterol,molecular docking study was performed. Results: Extensive DNA damage in acute study and a significant increase in levels of p-MAPKs',c-fos,c-jun,and EGFR was observed in N-diethylnitrosamine (200 mg/kg bw) and ferric nitrilotriacetate (9 mg/kg bw) alone treated rats. Rats which are pretreated with 20 mg/kg bw of β-sitosterol reduced the DNA damage and restored the elevated levels of above-mentioned markers (p < 0.05). The binding free energy obtained for β-sitosterol for ERK-2 was found to be-5.578. Conclusion: Therefore,it has been concluded that β-sitosterol has a strong potential against genotoxic as well as suppress neoplastic transformation in experimental renal cancer.