Drug-induced acute kidney injury is a serious disorder. Oxidative stress has a key role in its initiation and progression. In this study, the possible ameliorative effect of fimasartan against methotrexate-induced nephrotoxicity was investigated in comparison with α-tocopherol in rats. Wistar rats were allocated into six groups and treated as follows: group Ӏ received water on a daily basis for 8 successive days; group ӀӀ received methotrexate (20 mg/kg) on day 1, followed by water for 7 successive days; group ӀӀӀ received fimasartan (3 mg/kg/day) for 7 successive days; group IV received α-tocopherol (1 g/kg/day) for 7 successive days; group V received methotrexate (20 mg/kg) on day 1, followed by fimasartan (3 mg/kg/day) for 7 successive days; and group VI received methotrexate (20 mg/kg) on day 1, followed by α-tocopherol (1 g/kg/day) for 7 successive days. Finally, after euthanization of each animal by diethyl ether, the samples were collected for analysis. Administration of fimasartan and α-tocopherol resulted in a significant decline in serum creatinine and urea, a significant reduction of renal malondialdehyde, and a significant elevation of renal superoxide dismutase-1 compared to the methotrexate-treated rats. In conclusion, fimasartan has ameliorative effects, comparable to those of α-tocopherol, on methotrexate-induced nephrotoxicity in rats.