This research aims to evaluate possible protective effect of both Verapamil (VER) (150 mg⁄kg) and Famotidine (FAM) (40 mg⁄kg) on methotrexate (MTX) (5mg⁄kg) induced hepatotoxicity in rats. Forty adult male rats were divided into 5 groups; (n= 8). Group 1 received saline (control). Group 2 was subjected to single dose of MTX. Groups 3 and 4 were treated with VER and FAM respectively. Group 5 was treated with combined VER and FAM. At the end of treatment, the impacts of MTX on the hepatic damage and its prevention by VER and FAM were assessed by estimation of serum AST, ALT, total protein and albumin. Additionally, hepatic SOD activity, NO, MDA and TNF levels were measured in liver homogenates. MTX administration resulted in significant increases in ALT, AST, NO, MDA and TNF levels and reduces serum albumin, total protein and SOD levels; as well as severe inflammation and congestion in liver tissues compared to normal control group. On the other hand, treatment with VER and FAM ameliorated histopathological and biochemical deterioration induced by MTX. The oxidative stress plays an important role in MTX-induced hepatotoxicity in rats. Effects of VER on different parameters were better than FAM, while its combination was the best.