Oxidative damage in the brain may lead to cognitive impairments in aged humans. Further, in age-associated neurodegenerative disease, oxidative damage may be exacerbated and associated with additional neuropathology. Epidemiological studies in humans show both positive and negative effects of the use of antioxidant supplements on healthy cognitive aging and on the risk of developing Alzheimer disease (AD). This contrasts with consistent behavioral improvements in aged rodent models. In a higher mammalian model system that naturally accumulates human-type pathology and cognitive decline (aged dogs), an antioxidant enriched diet leads to rapid learning improvements, memory improvements after prolonged treatment and cognitive maintenance. Cognitive benefits can be further enhanced by the addition of behavioral enrichment. In the brains of aged treated dogs, oxidative damage is reduced and there is some evidence of reduced AD-like neuropathology. In combination, antioxidants may be beneficial for promoting healthy brain aging and reducing the risk of neurodegenerative disease.