Obesity is one of the major global health problems. Melatonin deficiency has been demonstrated to correlate with obesity. The aim of the study was to estimate the effect of melatonin on oxidative stress and adipokine levels in obese patients on a calorie-restricted diet. Thirty obese patients were supplemented with a daily dose of 10 mg of melatonin (n = 15) or placebo (n = 15) for 30 days with a calorie-restricted diet. Serum levels of melatonin, 4-hydroxynonenal (HNE), adiponectin, omentin-1, leptin, and resistin, as well as erythrocytic malondialdehyde (MDA) concentration and Zn/Cu-superoxide dismutase, catalase, and glutathione peroxidase (GPx) activities, were measured at baseline and after supplementation. Significant body weight reduction was observed only in the melatonin group. After melatonin supplementation, the adiponectin and omentin-1 levels and GPx activities statistically increased, whereas the MDA concentrations were reduced. In the placebo group, a significant rise in the HNE and a drop in the melatonin concentrations were found. The results show evidence of increased oxidative stress accompanying calorie restriction. Melatonin supplementation facilitated body weight reduction, improved the antioxidant defense, and regulated adipokine secretion. The findings strongly suggest that melatonin should be considered in obesity management. This trial is registered with CTRI/2017/07/009093.