Ancient traditions showed that fermented enzyme foods have beneficial health effects on the body. However, only a few studies have reported on its impact on weight loss and metabolic syndrome. Therefore, it is necessary to verify whether diet supplementation with fermented enzyme foods can have a beneficial functional impact on the body. We examined the antiobesity properties of fermented mixed grain (FMG) with digestive enzymes (FMG) in diet-induced obese mice. Sixty C57BL/6J mice were randomly assigned to six dietary groups: (1) normal diet (ND), (2) high-fat diet (HFD), (3) Bacilus Coagulans, (4) steamed grain, (5) low-dose FMG (L-FMG), and (6) high-dose FMG (H-FMG) supplement for 12 weeks. The results showed that H-FMG supplement dramatically decreased body weight and fat mass with simultaneous decreases in plasma lipid contents. Furthermore, H-FMG significantly lowered fasting blood glucose concentrations and improved glucose tolerance compared with the HFD group. Also, the concentrations of inflammatory cytokines secreted from adipocytes in H-FMG-supplemented mice decreased dramatically. Taken together, our findings indicated that H-FMG can ameliorate HFD-induced obesity and its associated complications and could be used as a potential preventive intervention for obesity.