Background and aims: Cyclophosphamide (CP), is a widely used cytotoxic alkylating agent with antitumor and immunosuppressant properties. In spite of its therapeutic importance, a wide range of adverse effects including reproductive toxicity has been demonstrated following CP treatment in humans and experimental animals. This drug has serious side effects such as inducing genotoxic effects, renal and hepatic damage Therfore The current report was designed to investigate the possible protective effect of Heracleum persicum against cyclophosphamide(CP)-induced hepatotoxicity in rats. Methods: In this experimental research, 30 male albino Wistar rats, with body weights of 180-200 g were obtained. The animals were randomly assigned into five groups of 6 in each.Group 1 (control) group 2 (only receiving cyclophosphamide) and groups 3, 4, 5 (receiving cyclophosphamide with different doses of methanol extract of H. persicum). In order to induce liver toxicity in groups 2, 3, 4 and 5, CP was administered as a single dose (0.5 mg/kg), intraperitoneally and methanol extracts (0.5, 1 and 2 mg/Kg) wereadministered by gavage in 24-h cycles over a 21-day period. Results: The results showed that administration of CP induced hepatic damage associated with significant increase in the serum marker enzymes aspartate and alanine transaminases (AST, ALT) and alkaline phosphatase (ALP) level in the CP treated group in comparison with the control (P<0.05). In addition, it was revealed that CP-administration cause a significant decrease (P<0.05) in activity of catalase (CAT) and superoxide dismutase (SOD). However, groups which received the extract of H. persicum in association with CP represented significantly improved parameters. Conclusion: The results revealed that the methanol extract of H. pesicum has hepatoprotective effect against cyclophosphamide(CP)-induced toxicity in rats.