Background: The liver is the major detoxification organ that deactivates and removes toxic chemicals. The oxidative stress-mediated toxicity of chemicals involves destruction primarily to liver tissue (Hepatotoxicity), which could lead to cancer. Diosgenin, a steroidal sapogenin, is reported to be an apoptosis inducer, antineoplastic and antioxidant. The present study is aimed to screen diosgenin for its effect on diethylnitrosamine induced hepatotoxicity in rats. Materials and Methods: 48 male Wistar rats were divided into 6 groups of 8 animals each. Group 1: the vehicle was given to the animals for 8 weeks. Group 2: den control, group 3 sorafenib, groups 4, 5, and 6 diosgenin (10, 20, and 40 mg/kg, respectively). Groups 2 to 6 were administered with 0.01% den in drinking water for 8 weeks. The respective treatment started from 4 th week and continued till the 11 th week. At the end of the study, animals were sacrificed for the determination of biochemical, antioxidant, and histological parameters. Results: Administration of den caused a significant increase in the levels of serum AST, ALT, ALP, LDH, and liver malondialdehyde as compared with control while the levels of glutathione, catalase, and superoxide dismutase were significantly decreased. Oral supplementation of diosgenin led to a significant decrease in the levels of AST, ALT, ALP, LDH, and malondialdehyde and increased the levels of glutathione, catalase, and superoxide dismutase. The liver histology of diosgenin administered groups was preserved. Conclusion: Diosgenin was found to prevent, slow, and treat the occurrence of hepatotoxicity.