A.A.); shaoyingai@21cn.com (S.A.); Tel.: +86-186-8050-4072 (M.M.-F.); +967-777766831 (A.A); +86-020-3288-5970 (S.A.) † These authors contributed equally to this work.Abstract: Biotic stress causes immense damage to agricultural products worldwide and raises the risk of hunger in many areas. Plants themselves tolerate biotic stresses via several pathways, including pathogen-associated molecular patterns (PAMPs), which trigger immunity and plant resistance (R) proteins. On the other hand, humans use several non-ecofriendly methods to control biotic stresses, such as chemical applications. Compared with chemical control, melatonin is an ecofriendly compound that is an economical alternative strategy which can be used to protect animals and plants from attacks via pathogens. In plants, the bactericidal capacity of melatonin was verified against Mycobacterium tuberculosis, as well as multidrug-resistant Gram-negative and -positive bacteria under in vitro conditions. Regarding plant-bacteria interaction, melatonin has presented effective antibacterial activities against phytobacterial pathogens. In plant-fungi interaction models, melatonin was found to play a key role in plant resistance to Botrytis cinerea, to increase fungicide susceptibility, and to reduce the stress tolerance of Phytophthora infestans. In plant-virus interaction models, melatonin not only efficiently eradicated apple stem grooving virus (ASGV) from apple shoots in vitro (making it useful for the production of virus-free plants) but also reduced tobacco mosaic virus (TMV) viral RNA and virus concentration in infected Nicotiana glutinosa and Solanum lycopersicum seedlings. Indeed, melatonin has unique advantages in plant growth regulation and increasing plant resistance effectiveness against different forms of biotic and abiotic stress. Although considerable work has been done regarding the role of melatonin in plant tolerance to abiotic stresses, its role in biotic stress remains unclear and requires clarification. In our review, we summarize the work that has been accomplished so far; highlight melatonin's function in plant tolerance to pathogens such as bacteria, viruses, and fungi; and determine the direction required for future studies on this topic.