Nuclear factor erythroid 2-related factor 2 (Nrf2) is considered as the sensor of oxidative stress, and the main aim of this signaling pathway is to maintain physiological condition by induction of redox balance. Also, this pathway exerts anti-inflammatory effects via antioxidant response element. Oxidative stress is a key factor in a variety of pathological conditions and high level of oxidative stress is associated with damages in lipids, proteins, genetic material, and cell membrane. Multiple drugs have been developed in order to diminish oxidative stress. However, synthetic drugs suffer from various drawbacks such as high cost and side effects. On the other hand, naturally occurring compounds are of interest due to their minimal side effects and valuable biological activities. Melatonin is a hormone of pineal gland which is found in different plants. This compound has a variety of favorable biological and therapeutic activities such as antioxidant, anti-inflammatory, anti-tumor, anti-diabetic, and cardioprotection. At the present review, we demonstrate that Nrf2 signaling pathway explains some of the therapeutic and biological effects of melatonin.