Methotrexate is an effective anticancer and immunosuppressive agent. However, nephrotoxicity is one of the complications of its use. On the other hand, curcumin, a naturally occurring polyphenolic compound, is reported to have antioxidant and anti‐inflammatory properties. Those two properties are likely to prevent methotrexate‐induced nephrotoxicity. The aim of this study is to evaluate the possible protective effect of curcumin against methotrexate‐induced nephrotoxicity and delineate various mechanism(s) underlies this effect in rats. Nephrotoxicity was induced in Wistar rats by intraperitoneal administration of methotrexate (7 mg/kg/day) for three consecutive days. Curcumin administration in methotrexate‐intoxicated rats resulted in nephroprotective effects as evidenced by the significant decrease in levels of serum creatinine and urea as well as renal malondialdehyde, nitric oxide, and tumor necrosis factor‐α with a concurrent increase in renal glutathione peroxidase and superoxide dismutase activities compared to nephrotoxic untreated rats. Additionally, immunohistochemical analysis demonstrated that curcumin treatment markedly reduced cyclooxygenase‐2 expression. Histopathological examination confirmed the protective effects of curcumin. In conclusion, curcumin protected rats from methotrexate nephrotoxicity, at least in part, through its antioxidant and anti‐inflammatory activities.