Heavy metal (HM) accumulation is a growing environmental concern that affects the growth and development of plants and poses a risk to human health. When taken up by plants, HM causes severe damage, including oxidative damage, hampered physiological processes, disrupted ion homeostasis, and metabolic imbalance. Plants tackle HM stress through innate defense mechanisms, such as immobilization of HM ions, their chelation by phytochelatins and metallothioneins, limited foliar translocation, metal sequestration and compartmentalization, metal exclusion, and free radicals scavenging by antioxidant enzymes. Melatonin (MT), a natural plant hormone, has been observed to exhibit multifaceted protection under HM stress. MT enhances plant tolerance to HM stress by improving redox and nutrient homeostasis, metabolic functions, and osmotic balance. It is imperative to elucidate the mechanisms by which both exogenous and endogenous MT mitigate HM toxicity in plants to recognize potential knowledge gaps that should be addressed in the future. This chapter focuses on providing better insights into the MT-mediated HM stress response and tolerance mechanisms in plants, including MT-mediated HM chelation, immobilization and sequestration, oxidative damage reduction, and transcriptional and epigenetic regulation of HM stress.