Melatonin (MLT) is an amine hormone secreted mainly by the pineal gland. The main physiological function of MLT is to regulate the circadian rhythm. Recent studies have shown that MLT could affect the immune system through several ways to regulate the function of immune system. In infectious diseases, MLT can regulate the number of immune cells and the expression of cytokines. Moreover, MLT may enhance the function of the immune system by reducing the secretion of inflammatory factors, down-regulating the adhesion of leukocytes and anti-oxidation, which may reduce the pathology caused by inflammation damage. Meanwhile, MLT could play a role against pathogens infection by directly inhibiting the replication and proliferation of pathogens. Therefore, MLT may be considered as a novel target and a new method for the clinical treatment of infectious diseases. This article reviews the progress of the effects and mechanisms of MLT in regulating the immune system and the important role in infectious diseases.