The liver continuously produces free radicals and reactive oxygen species (ROS) as part of metabolic process. These free radicals are neutralized by an elaborate antioxidant defense system consisting of enzymes and numerous nonenzymatic antioxidants like flavonoids. In this study, we have evaluated effects of melatonin and caffeic acid phenethyl ester (CAPE) to young and aged rat liver. Aging-related hepatic changes examined by light and electron microscopy and biochemical methods. Melatonin and CAPE decreased tissue malondialdehyde (MDA) levels in aged rats. Melatonin elevated tissue glutathione peroxidase (GSH-Px) activity and tGSH level, whereas CAPE elevated tissue catalase activity in aged rats. This study demonstrates that both melatonin and CAPE are beneficial in delaying age-related hepatocellular changes. Melatonin and CAPE supplementation in older ages may support liver to protect itself from various damaging agents including infectious agents and toxins.