Uncontrolled intracellular generation and accumulation of reactive oxygen species (ROS) can alter the body’s homeostasis. The resulting oxidative stress has been considered as a root of aging and many age-associated human disorders. These include Alzheimer disease, atherosclerosis, coronary heart disease, chronic obstructive pulmonary disease, diabetes, etc. It is noticeable that the aging process attenuates adaptive response to oxidative stress. Moreover, oxidative damage to DNA can cause mutagenic change, which potentially initiates cancer development. Numerous small molecules including antioxidant vitamins have exhibited therapeutic potential in preclinical studies. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) is the master regulator of cellular cytoprotective defenses, including the carcinogen detoxification, protection against oxidative stress and inflammation, a maintenance of stability of proteins and removal of damaged proteins via proteasomal degradation or autophagy. NRF2 may also play a role in regulating species longevity as well as preventing carcinogenesis. Thus, a constitutively upregulated cytoprotective response mediated by NRF2 is commonly observed in naturally long-lived species and experimental models of extension to lifespan. In this context, NRF2 is the guardian of healthspan, protecting against many age-related pathogenic complications. The transcriptional activity of NRF2 and its target gene expression are likely to decline with aging. Use of NRF2 activators by natural products may be a viable approach for improving health- related outcomes.