Introduction: In the scenario of non-communicable chronic diseases, obesity has briefly impacted the global population, causing serious public health problems. There are approximately 2.0 billion overweight and obese people in the world. Brazil ranks fifth in the world with approximately 18.0 million people. Research has advanced on the physiological role of melatonin (MEL) as a therapeutic agent for the treatment of obesity. Objective: It was to highlight the main clinical outcomes of melatonin regulation in obesity through a systematic review of the literature. Methods: The present study followed a concise systematic review model, following the systematic review rules (PRISMA). The literary search process was carried out from September to October 2022 and developed based on Scopus, PubMed, Science Direct, Scielo, and Google Scholar. The low quality of evidence was attributed to case reports, editorials, and brief communications, according to the GRADE instrument. The risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: It was founded 139 studies were submitted to the eligibility analysis, then, 46 of the 54 total studies were selected for this systematic review. According to the GRADE instrument, most studies showed homogeneity in their results, with I2 =98.4% >50%. Studies have shown an important role for melatonin in metabolic diseases such as obesity, type 2 diabetes mellitus, and metabolic syndrome. It is possible to define some pathological syndromes related to MEL and discuss general guidelines for clinical therapy. However, there is still no consensus on the possible role of melatonin as an adjuvant in the treatment of metabolic diseases. More studies are needed to define the possible risks and benefits of melatonin as a therapeutic agent. Furthermore, several precautions must be taken into account, such as restricting the administration of chronic melatonin to the night, carefully choosing the time of administration according to the desired effect, and adapting the dosage and formulation individually to build a melatonin blood profile that mimics the physiological and ends early in the morning.