Oxidative stress plays multiple roles in the pathobiology of several neurodegenerative disorders and Alzheimer’s disease in particular. Increased oxidative stress in the brain is suggested to be associated with aging, greater amounts of easily oxidizable unsaturated fatty acids, higher utilization of oxygen by the brain, mitochondrial-derived free radicals, calcium homeostasis, and glutamate-induced excitotoxicity. Moreover, environmental chemicals/toxins, heavy metals, and an imbalanced diet might increase oxidative stress potentially leading to a decrease in cognitive functions. Cellular health is also dependent on the levels of nicotinamide adenine dinucleotide (NAD+). It has been well documented that NAD+ is an important coenzyme for over 400 different oxidoreductases and turns out to be a relevant factor to the oxidative stress in the brain. Since the last two decades, NAD+ has been shown to be more than a mere regulator of metabolism, but rather may play a key role in the aging process. NAD+ along with sirtuins are important for various neurophysiological functions, and depletion of NAD+ may be associated with compromised physiological and cognitive functions. To protect the brain from oxidative stress, a modest endogenous protective system works in the brain through dedicated enzymatic machinery. Key enzymes are superoxide dismutase and catalase, which provide protection against oxidative stress. Aging, various neurological disorders, and chronic inflammation might also affect the levels of these protective enzymes and reduce their levels. Natural compounds, including polyphenols, can offer protection through NAD+ and various other mechanisms. Based on these factors it is becoming more and more clear that oxidative stress and its devastating effects on cognitive decline represents a major health issue in neurobiology. There is a need to identify potential compounds and therapeutic targets for mitigating oxidative stress and/or to strengthen the protective endogenous mechanisms. Novel approaches aiming to support and provide protective mechanisms in the brain will represent a great success in therapeutics. We welcome all article types focusing on the analysis and investigation of oxidative stress - originated from different sources - and its impairing effects on the brain. We will also accept studies investigating naturally occurring compounds, standard medications, and nutraceuticals that have an impact on oxidative stress, NAD+ metabolism and medical and health applications. For this, the aim of this Research Topic is to provide novel insights on oxidative stress (induced by any mechanism) impact on brain health, and on the strengthening of brain-protective mechanisms, supporting cognitive functions.