Melatonin (N-acetyl-5-methoxytryptamine) is a circadian hormone produced in vertebrates by the pineal gland and other organs. Melatonin is believed to influence immune cells leading to modulation of the proliferative response of stimulated lymphocytes as well as cytokine production. Due to the antioxidant and immunomodulatory effects of melatonin, it is suggested that this molecule could be a therapeutic alternative agent to fight bacterial, viral, and parasitic infections by a variety of mechanisms. Herein, we review the effects of melatonin on the cell biology of protozoan parasites and host's immune response. In toxoplasmosis, African trypanosomiasis and Chagas’ disease, melatonin enhances host's immune response against the parasite via regulating the secretion of inflammatory mediators. In amoebiasis, melatonin reduces the amoebic lesions as well as increasing the leukophagocytosis and the number of dead amoebae. In giardiasis, serum melatonin levels are elevated in these patients; this suggests a positive correlation between the level of melatonin and phagocytic activity in the G. duodenalis infected patients, possibly related to melatonin’s immunomodulatory effect. In leishmaniasis, melatonin arrests parasite replication accompanied by releasing mitochondrial Ca²⁺ into the cytosol, increasing the level of mitochondrial nitrites as well as reducing superoxide dismutase (SOD) activity. In malaria, melatonin synchronizes the Plasmodium cell cycle via modulating cAMP-PKA and IP3-Ca²⁺ pathways. Thus, simultaneous administration of melatonin agonists or giving pharmacological doses of melatonin may be considered a novel approach for treatment of malarial infection.