Acetaminophen is an analgesic and antipyretic drug, its overdose cause hepatotoxicity. The current antidote for acetaminophen hepatotoxicity is N-acetyl cysteine (NAC); however, NAC has been resulted in severe side effects as seizures, intracranial hypertension and cerebral edema. This study aimed to assess and compare the ameliorative effects of cimetidine and silymarin against acute acetaminophen–induced hepatotoxicity. Fifty four adult albino rats were divided into nine groups: negative control; solvent control; silymarin control; cimetidine control; cimetidine and silymarin control; acetaminophen group; acetaminophen and silymarin group; acetaminophen and cimetidine group; acetaminophen, cimetidine and silymarin group. A single dose of: acetaminophen (800 mg/kg, orally); silymarin (150mg/kg, orally) and cimetidine (150 mg/kg, intraperitoneally) were given according to study regimen. Liver histopathology, biochemical analysis of liver aminotransferases (AST & ALT) and hepatic tissue levels of oxidative stress index (MDA) and antioxidant (GSH) were assessed. Treatment with cimetidine alone gave better biochemical results as compared to treatment with silymarin alone. However combined treatment with cimetidine and silymarin showed better ameliorative effects than either of them given alone, evidenced by better improvement in histopathological examination and biochemical results as compared to other tested groups, and these results were non-significant as compared to controls. In conclusion treatment with silymarin and cimetidine in-combination for acute acetaminophen–induced hepatotoxicity showed better improvement probably due to synergistic hepatoprotective effects.