Melatonin, a hormone secreted by the pineal gland, works directly and indirectly as a free radical scavenger. Its other physiological or pharmacological activities could be dependent or independent of receptors located in different cells, organs, and tissues. In addition to its role in promoting sleep and circadian rhythms regulation, it has important immunomodulatory, antioxidant, and neuroprotective effects suggesting that this indole must be considered as a therapeutic alternative against infections. The aim of this review is to describe the effects of melatonin on oxidative stress and the resistance to bacterial (Klebsiella pneumoniae, Helicobacter pylori, Mycobacterium tuberculosis, and Clostridium perfringens), viral (Venezuelan equine encephalomyelitis virus and respiratory syncytial virus), and parasitic (Plasmodium spp., Entamoeba histolytica, Trypanosoma cruzi, Toxoplasma gondii, and Opisthorchis viverrini) infections.