The current study was designed to explore the protective impact of silymarin (SIL) against the hepatotoxicity induced by daily treatment with flutamide (FLU), for one month, in intact male rats. Two different doses of FLU, one was low and corresponds to the human therapeutic dose (10 mg/kg) and the other was high and corresponds to ½ lowest lethal dose (500 mg/kg) were applied. Obtained results showed that oral administration of FLU in male rats significantly increased hepatic malonic dialdehyde (MDA), and markedly decreased hepatic reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-s-transeferase (GST). In parallel, activities of alanine aminotranseferase (ALT), aspartate aminotranseferase (AST) and alkaline phosphatase (ALP), and level of total bilirubin in serum were significantly elevated; while serum total proteins, albumin and globulin, and hepatic total proteins were decreased in FLU-treated animals. Also, significant increases in serum and liver contents of total lipids (TL), total cholesterol (TC) and triglycerides (TG), and serum low density lipoproteins-cholesterol (LDL-c), which accompanied with decrease in serum level of high density lipoproteins-cholesterol (HDL-c) following administration of FLU. The adverse effects of FLU on measured parameters appeared to be dose-dependent. Treatment with SIL (50 mg/kg) in rats given FLU (10 mg or 500 mg/kg) greatly improved the levels of investigated biomarkers of liver status. However, the beneficial effect of SIL was more remarkable in rats receiving FLU at a dose of 10 mg/kg. Obtained biochemical changes induced by the two used doses of FLU and the ameliorative impact of SIL were confirmed by histopathological examinations of liver sections of treated rats. In conclusion, SIL can be used effectively in the protection against hepatotoxicity induced by FLU.