Melatonin is a neurohormone synthesized in the human pineal gland. Melatonin is considered a multifunctional molecule associated with circadian rhythm regulation, impacting metabolism, the immune system, sleep, antioxidant, anti-inflammatory, and anti-apoptotic properties. Melatonin functions as a free radical scavenger, directly neutralizing reactive oxygen species (ROS) and nitrogen-derived species. Dietary patterns rich with fruits and vegetables are reported to enhance melatonin levels, where the gut microbiota plays a crucial role in melatonin production from tryptophan. The neuroprotective role of melatonin is facilitated through Erk1/2 dependent nuclear factor E2-related factor 2 (Nrf2). Erk1/2 plays a paradoxical role where Erk1/2 enhances the generation of mitochondrial ROS and concurrently reduces ROS-induced damage by regulating mitochondrial homeostasis. Intriguingly, this dual activity of Erk1/2 is reported to be orchestrated via Nrf2, promoting neuroprotection. This chapter aims to explore the molecular function of melatonin in the regulation of ERK1/2-dependent Nrf2 activation, Keap1 and Bach1 regulation, and downstream expression of cytoprotective genes, including HO-1, NQO1, and GCLC, as well as the interplay between food and gut microbiota in modulating melatonin levels that contribute to neuroprotection.