Cisplatin is a widely used anticancer drug but, it can produce undesirable effects such as hepatotoxicity even in therapeutic doses. The underlying mechanism in hepatotoxicity has been attributed to free oxygen radicals. The present study was designed to determine the possible protective effects of grape seed extract (GSE) and Origanum onites essential oil (OOEO) on liver toxicity induced by cisplatin. Ninetysix-male Wistar albino rats were divided into eight groups, twelve in each (Control, GSE, OOEO, GSE+OOEO, Cisplatin, GSE+ Cisplatin, OOEO+ Cisplatin, GSE+OOEO+ Cisplatin) and followed up for 10 days. Cisplatin and OOEO were injected intraperitoneally. GSE was administered with gavage. The histopathological examination of liver tissues was performed by light microscope. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) levels were determined in liver tissues. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured in serum. Cisplatin-induced considerable hepatocyte damage under microscopic examination, and an increase in MDA levels as well as a decrease in the activities of antioxidant enzymes, including SOD, GSH-Px in liver tissues and an increase in serum ALT and AST (p < 0.001). The addition of GSE and/or OOEO significantly prevented microscopic tissue damage, reversed oxidative stress parameters and biochemical values compared to the cisplatin group (p < 0.001). In conclusion GSE and OOEO may be used in adjuvant therapy to prevent cisplatin-induced hepatotoxicity, but further studies using various doses, different time intervals, and a larger number of animals need to be carried out.