Various forms of abiotic stresses, including salt, water (excess or scarcity), UV light, temperature, and heavy metals (HMs), cause a reduction in plant growth and productivity. Exposure to HMs is among the most detrimental forms of abiotic stress. Several anthropogenic activities have caused a considerable increase in the accumulation of HMs in almost all biological systems, leading to HMs pollution. Heavy metals severely hinder plant development and productivity in agro-ecosystems, which is a major threat to achieving the sustainable agriculture goal. The non-biodegradable nature of HMs and their accumulation may affect various biological processes in plants that include photosynthesis, the antioxidant defense system, mineral nutrition, and phytohormone production. Some HMs may have toxic effects due to their nature to impact some endogenous molecules like phytohormones, which can negatively affect a plant’s ability to grow, develop, and reproduce. Exogenous application of some regulatory molecules, like melatonin, may protect the plants against the harmful effects of HMs. On the one hand, melatonin is known to immobilize HMs in cell walls and sequester them in vacuoles to directly reduce HMs-induced toxicity in plants; on the other hand, it also helps in improving photosynthesis, antioxidant defense system, nutrient uptake, and accumulation of compatible solutes to save the plants from HMs-induced toxicity indirectly. Further, it regulates the expression of key genes to confer better HM stress tolerance to plants. This chapter is, therefore, an attempt to present up-to-date information on the role of melatonin-mediated HMs stress amelioration in plants to improve crop productivity.