This review summarizes that NPs from natural sources can regulate Nrf2 antioxidant pathway to exert a wide spectrum of health-promoting effects in vitro and in vivo, such as liver protection, kidney protection, lung protection, neuroprotection, cardioprotection, gastrointestinal protection, anti-oxidation, anti-diabetic, anti-aging, anti-inflammation, anti-radiation, anti-depression, anti-cancer, anti-atherosclerosis, immunomodulation, and improving reproductive function. The gene discussed is NFE2L2; the disease is major depressive disorder.