Methotrexate (MTX), a structural analogue of folic acid, is widely used as a chemotherapeutic drug in various malignancies and inflammatory diseases. MTX treatment is often limited by severe side effects; liver damage is one of the major toxic effects of MTX. This study was designed to investigate whether curcumin had a protective effect on methotrexate-induced liver damage and oxidative stress. We divided 49 Wistar strain rats into 7 groups (n = 7) during 8 days of treatment: group 1, control; group 2, dimethyl sulfoxide as a vehicle drug; group 3, MTX-treated (20 mg/kg-1); group 4, curcumin (100 mg/kg-1); group 5, curcumin (200 mg/kg-1); group 6, curcumin (100 mg/kg-1) with MTX-treated; group 7, curcumin (200 mg/kg-1) with MTX-treated. All animals were killed 4 days after intraperitoneal injection of MTX, and liver tissue was obtained for histopathologic examination and to study glutathione peroxidase (GPx), superoxide dismutase (SOD), and malondialdehyde (MDA) levels; on the other hand, total antioxidant status (TAS), aminotransferase (AST), and alanine aminotransferase (ALT) were measured in serum. Administration of curcumin decreased the liver damage and MDA level, and data showed that GPx and SOD levels in liver were increased (P < .05) by MTX treatment. The levels of TAS, AST, and ALT were significantly increased in serum (P <.05). These results show that curcumin may protect the liver of rats from methotrexate-induced injury and its antioxidant effects may have therapeutic benefit against MTX cytotoxicity.