In this study, we investigated the effects of silybin on body weight and glucose tolerance in mice fed high fat diet mice. We found that body weight, plasma TG contents, fat size, glycerol, 3-hydroxybutyrate and total cholesterol were significantly decreased in silybin (500 mg/kg) supplemented groups compared to high fat diet group. Whereas, total food intake was not changed between high fat diet group and high fat diet plus silybin group. Futhermore, supplement of high fat elevated the glucose intolerance and was improved in silybin supplement group. Finally, we examined the effect of silybin on circulating adipocytokine level to explore the possible mechanism by which silybin improves high fat diet-induced obesity and diabetes. The silybin supplement significantly reduced the level of adipocytokine, such as leptin, resistin, IL-6, and MCP-1 induced by high fat diet. These results suggest that silybin can be used to improve obesity and diabetes.