The postharvest deterioration of mango fruits is a critical issue limiting mango storage and preservation due to its climacteric nature. This study evaluated the storage behavior of two mango cultivars and their response to exogenous melatonin (MT, 1000 μmol L⁻¹) treatment in attenuating fruit decay and enhancing fruits’ physiological and metabolic processes and gene relative expression subjected to cold storage. MT treatment in both mango cultivars significantly delayed weight loss, firmness, respiration rate, and decay incidence. However, MT did not influence the TSS, TA, and TSS:TA ratio regardless of the cultivar. Moreover, MT inhibited the decrease in total phenol and flavonoid content and AsA content while delaying the increase in the MDA content of mango during storage in both cultivars. In addition, MT dramatically inhibited the enzyme activity of PPO. In contrast, an increase in the activities of antioxidant enzymes (SOD and APX) and PAL and their genes’ relative expression was noticed in MT-treated fruits versus control in both cultivars. However, MT treatment was cultivar dependent in most parameters under study. These results demonstrated that MT treatment could be an essential postharvest treatment in minimizing decay, maintaining fruit quality, and extending mango fruits’ postharvest shelf life by enhancing the physiological and metabolic processes during cold storage.