Walnut (Juglans regia L.) is extensively used in traditional systems of medicine for treatment of various ailments. It is described as an anticancer, tonic, blood purifier and detoxifier agent. The present study was undertaken to investigate modulatory effects of walnut extract on the toxicity of an anticancer drug, cyclophosphamide (CP) with special reference to protection against disruption of drug metabolizing and antioxidant enzymes. Plant extract+CP group animals showed restoration in the level of cytochrome P450 (CYP) content and in the activities of glutathione S-transferase (GST), glutathione peroxidase (GP) and catalase (CAT) in both liver and kidneys. But plant extract restored the activity of superoxide dismutase (SOD) and the level of reduced glutathione (GSH) in the kidneys only when compared with CP-treated animals. Plant extract treatment alone caused significant reduction in the content of CYP in the kidneys mainly. The extract showed a significant increase in the level of GSH and in the activities of GP in both the tissues and CAT in liver only, whereas no significant change was observed in the activities of GST and SOD. CP treatment resulted in a significant (P < 0.01) increase in the lipid peroxidation (LPO) in the liver and kidneys compared with controls, while the extract+CP treated group showed a significant decrease in the LPO in liver and kidneys when compared with the CP-treated group. The study shows that the use of J. regia extract might be helpful in abrogation of CP toxicity during the chemotherapy.