ABSTRACT: Melatonin is a multifunctional signaling molecule that is ubiquitously distributed in different parts of a plant and responsible for stimulating several physio-chemical responses to adverse environmental conditions. In this review, we show that, although plants are able to biosynthesize melatonin, the exogenous application of melatonin to various crops can improve plant growth and development in response to various abiotic and biotic stresses (e.g., drought, unfavorable temperatures, high salinity, heavy metal contamination, acid rain, and combined stresses) by regulating antioxidant machinery of plants. Current knowledge suggests that exogenously applied melatonin can enhance the stress tolerance of plants by regulating both the enzymatic and non-enzymatic antioxidant defense systems. Enzymic antioxidants upregulated by exogenous melatonin include superoxide dismutase, catalase, glutathione peroxidase, and enzymes involved in the ascorbate-glutathione cycle (ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, and glutathione reductase), whereas levels of non-enzymatic antioxidants such as ascorbate, reduced glutathione, carotenoids, tocopherols, and phenolics are also higher under stress conditions. The enhanced antioxidant system consequently exhibits lower lipid peroxidation and greater plasma membrane integrity when under stress. However, these responses vary greatly from crop to crop and depend on the intensity and type of stress, and most studies to date have been conducted under controlled conditions. This means that a wider range of crop field trials and detailed transcriptomic analysis are required to reveal the gene regulatory networks involved in the between melatonin, antioxidants, and abiotic stress.