The chronobiological effects of melatonin which is mainly secreted by the pineal gland in the central nervous system are thoroughly known. However, beyond this knowledge, the role of melatonin in the physiology and pathologies of the gastrointestinal system (GIS) is also noteworthy. Melatonin is synthesized in large quantities from enterochromaffin cells in the GIS, independent from a photoperiodic rhythm. Melatonin synthesized from these cells shows widespread effects on peripheral tissues by binding to MT1 / MT2 receptors. Melatonin, as is well known, has a free radical scavenging role, except for receptor-dependent effects. It has also been reported to have regulatory roles on GIS motility and visceral sensation. The role of melatonin in gastrointestinal pathologies has being investigated for a long period, especially in esophagitis, gastric mucosal injury, peptic ulcer, irritable bowel syndrome, inflammatory bowel diseases, and necrotizing enterocolitis. In this context, the protective effects of melatonin in the GIS are markedly drawing attention nowadays. Yet until recently, melatonin itself and its agonists have only found clinical use in jet lag, insomnia, and depression accompanied by sleep deprivation. However, new findings are promising regarding the therapeutic potential of melatonin for GIS pathologies. This review reveals the role of melatonin in GIS physiology and pathologies in the light of the recent literature.