Consumption of an exceedingly high-fat diet with irregular eating and sleeping habits is typical in the current sedentary lifestyle, leading to chronic diseases like obesity and diabetes mellitus. Leptin is a primary appetite-regulating hormone that binds to its receptors in the hypothalamic cell membrane and regulates downstream appetite-regulating neurons NPY/AgRp and POMC in the hypothalamus. Based on the fat content of the adipose tissue, leptin is secreted, and excess accumulation of fat in adipose tissue stimulates the abnormal secretion of leptin. The secreted leptin circulating in the bloodstream uses its transporters to cross the blood-brain barrier (BBB) and reach the CSF. There is a saturation limit for leptin bound to its transporters to cross the BBB, and increased leptin secretion in adipose tissue has a defect in its transport across the BBB. Leptin resistance is due to excess leptin, a saturation of its transporters, and deficiency in either the receptor level or signalling in the hypothalamus. Leptin resistance leads to obesity due to excess food intake and less energy expenditure. Normal leptin secretion follows a rhythm, and alteration in the lifestyle leads to hormonal imbalances and increases ROS generation leading to oxidative stress. The sleep disturbance causes obesity with increased lipid accumulation in adipose tissue. Melatonin is the master regulator of the sleep-wake cycle secreted by the pineal gland during the night. It is a potent antioxidant with anti-inflammatory properties. Melatonin is secreted in a pattern called the circadian rhythm in humans as well. Research indicates that melatonin plays a vital role in hormonal regulation and energy metabolism, including leptin signalling and secretion. Studying the role of melatonin in leptin regulation will help us combat the pathologies of obesity caused by leptin resistance.