The reperfusion following liver ischemia results in hepatocyte damage and apoptosis. The aim of this study was to investigate the effects of two antioxidant agents, carnosine and melatonin, in rat liver ischemia-reperfusion injury. Five study groups were formed; I. sham, II. ischemia-reperfusion, III. ischemia-reperfusion+melatonin, IV. ischemia-reperfusion+carnosine, V. ischemia-reperfusion+melatonin+carnosine. Then 250 mg/kg carnosine and 10 mg/kg melatonin were administered intraperitoneally 30 min before ischemia and immediately after the reperfusion. Sinusoidal dilatation, congestion and neutrophil infiltration were observed in the ischemia-reperfusion group while these symptoms were less pronounced in the treatment groups. Alanine aminotransferase, aspartate aminotransferase and myeloperoxidase levels were increased in the ischemia-reperfusion group while they were lowered in the treatment groups. Glutathione level was low in the ischemia-reperfusion group while it tended to increase in the ischemia-reperfusion+carnosine administered and ischemia-reperfusion+carnosine+melatonin administered groups. There was an increase in the number of apoptotic cells in the ischemia-reperfusion group while this number was lowered in the treatment groups. Carnosine was more effective than melatonin in the reversal of structural and biochemical alterations that resulted from ischemia-reperfusion injury. The administration of melatonin and carnosine together yielded better outcomes compared to the sole administration of each agent.