Melatonin is not only found in animals but also in plants, where it is synthesized from the amino acid tryptophan. Plants, unlike animals, are sessile and susceptible to various biotic and abiotic stressors. These factors can occur alone in the environment or in conjunction with other stresses, such as heat and drought, drought and salt, heavy metal toxicity and senescence, and other abiotic and biotic stresses. These circumstances influence plant growth, development, and yield. Melatonin is synthesized in plants and has been suggested as an antioxidant, photoperiod regulator, growth stimulator, etc. Exogenous melatonin treatment protects against biotic and abiotic stresses such as high temperature, drought, cold, salt, oxidative stress, senescence, and so on. Melatonin’s role involves an independent effect or a synergistic effect with phytohormones or secondary signalling mediators such as NO, Ca2+, and H2S. Exogenous melatonin administration has previously been described for single stressors. However, more research is needed to determine the mechanism by which exogenous melatonin reduces combined stress. Therefore, this chapter discusses the role and mechanisms involved in the exogenous application of melatonin to alleviate combined stress in plants.