Oxidative stress is a key feature during progression of chronic neurodegenerative conditions such as Alzheimer's disease. In aging humans and animals, voluntary exercise lowers oxidative stress reactions. Additionally, recent work in our lab demonstrated that cognitive and physical stimulation (termed environmental enrichment) counteracts amyloid beta pathology, neurovascular dysfunction and behavioral symptoms in mice with Alzheimer-like disease. Based on these facts, we hypothesized that cognitive and physical activity can also protect against oxidative stress in Alzheimer-diseased brain. We, therefore, kept female TgCRND8 mice under standard and enriched housing from day 30 until 5 months of age. Environmental stimulation attenuated pro-oxidative processes and triggered anti-oxidative defense mechanisms as indicated by diminished biomarkers for reactive oxygen and nitrogen species, downregulation of pro-inflammatory and pro-oxidative mediators, decreased expression of pro-apoptotic caspases, and upregulation of SOD1 and SOD2. This study identifies a thus far undescribed antagonizing effect of environmental stimulation on Alzheimer's disease-related oxidative damage.