Obesity, a metabolic disorder is reaching an epidemic proportion and 20% increase in a normal body weight has been shown to be related to 20% increase in mortality rate. However, unsuccessful battle against this condition has led to the quest of finding a novel therapeutic agent (Timper and Brüning, 2017). Orlistat, a gastrointestinal lipase inhibitor has been recommended for the treatment of obesity. However, the gastrointestinal side effects have discouraged most patient from its continuous usage. Hence, there is a need for a more potent drug with less side effect (Jain et al., 2011). Melatonin, which are widely used alternative medicine have been reported to be effective in lowering the body weight with very little side effects. Therefore, the present study investigated the effects of melatonin in obesity model of male Wistar rats weighing between 110 – 130 g. It was hypothesized that melatonin is not an anti-obesitogenic therapy on obese rat model. Fifty (50) rats of ten (10) animals per group were divided into the following: control (untreated); high fat diet (HFD); high fat diet recovery (hfd); hfd + melatonin (4 mg/kg); and hfd + orlistat (30 mg/kg). Obesity was induced by exposing the rats to high fat diet for 16 weeks and confirmation was done using Lee index, which was determined by the formula: 4√body weight (g) / nose-anal length (cm). Rats with an index higher than 0.30 were considered obese and were used for the study (Adeyemi et al., 2020). Treatment started and lasted for 28 days after which the rats were anesthetized by intramuscular injection of 50 mg/kg of ketamine. Melatonin and orlistat were administered at 4 and 30 mg/kg b.w., p.o. respectively. Animals were cared for and used according to the University of Ilorin ethics guidelines. Diagnostic kits for the determination of the biomarkers were obtained from Abcam PLC, Cambridge, UK and the assays were performed according to the manufacturer’s instruction. Data were analyzed using analysis of variance and LSD post hoc test at 0.05 level of significance. The results showed that the induced obesity was accompanied with significant increases in plasma glucose, but significant decreases in plasma insulin. Relative to the obese control, treatments with melatonin caused significant elevations in total antioxidant capacity (TAC), catalase, superoxide dismutase (SOD) and gluthathione peroxidase (GPx), however, a significant decrease in interleukin 6 (IL-6) and tumor necrotic factor (TNF-a). Hence, it was concluded that melatonin could be beneficial in the management of obesity.