This research investigated the effect of co‐supplementation of selenium with zinc on weight control and the inflammatory and oxidative status in relation to obesity. Male Wistar rats (N = 32) were randomly divided into four groups after induction of obesity model: 1) “Zn” was supplemented with zinc sulfate (15 mg/kg BW), 2) “Se” supplemented with selenium as sodium selenate (0.5 mg/kg BW), 3) “Zn + Se” which received Zn (15 mg/kg BW) + Se (0.5 mg/kg BW), and 4) “HFD” as the control group. The intervention was done for eight weeks. At the end of treatment, serum and tissue level of Zn, Se, SOD, GSH‐Px, MDA, leptin, TNF‐α, and IL‐6 was evaluated. Weight and food intake were significantly reduced in the Se group(p < .001), while in the Zn group, weight gain due to obesity was prevented compared to the control group (p = .48). There was a significant and stronger increase in SOD, GSH‐Px levels and a remarkable decrease in MDA, leptin, TNF‐α, and IL‐6 in the group receiving the combination of two supplements than either alone(p < .001). Leptin had a positive correlation with inflammatory factors and lipid peroxidation marker and showed an inverse relationship with Zn and Se levels and anti‐oxidative enzymes(p < .05). The analysis showed the mediating role of leptin in the effects of zinc. Co‐supplementation of selenium and zinc may have a synergistic effect in reduction of oxidative and inflammatory markers. Regarding the effect of zinc on inflammatory factors and lipid peroxidation, leptin can play a mediating role.