The benefit of silymarin, a plant extract with strong antioxidant activity against hepatotoxicity induced by cisplatin in rats was investigated in this study. Cisplatin is one of the most effective chemotherapeutic drugs, yet it alone does not achieve a satisfactory therapeutic outcome and at high doses it can produce undesirable side effects. Five equal-sized groups (18 rats each) of male Sprague Dawley rats [control, vehicle; cisplatin; silymarin 2 h after cisplatin injection; and silymarin 2 h before cisplatin injection] were used. Histopathological and ultrastructural observation of livers were carried out using light and electron microscopy. Results documented that cisplatin produced behavioral, external features animal changes, as well as hazard pathological picture changes in liver where most hepatocytes appeared diminutive with vacuolated cytoplasm, sinusoids dilated and organelle disorganized. These results revealed that cisplatin may be toxic and terminates in complex liver damage. Administrations of silymarin 2 h after cisplatin, significantly increase the body weight returning it to normal, yet it failed in complete protection against the pathological alteration caused by cisplatin. Pretreatment with silymarin 2 h before cisplatin significantly decreased the pathological changes induced by cisplatin and appeared highly protective. These results suggested that silymarin possess protective effects against cisplatin hepatotoxic action in animal models. Since, no significant toxicity of silymarin is reported in human studies, this plant extract can be used as a dietary supplement by patients taking anticancerous medications and might serve as a novel combination agent with cisplatin since it plays a significant role in reducing its toxicity.