Natural products are getting much attractions to prevent and cure theses metabolic diseases. Investigation of therapeutic mechanisms of the natural products is necessary to use the natural products as complementary medicines. Recently, extract of Platycodon grandiflorum root (PGE) is known to have beneficial effects on obesity and diabetes. However, its detailed mechanism of anti-obesity and anti-diabetes effect is poorly understood. In this study, we investigated the anti-diabetic role of PGE by proteomic and bioinformatic analysis in the mice liver tissue. Mice were fed with 60% kcal of high fat diet (HFD) with or without 5% of ethanol extract of PG root. After 16 weeks of diet, mice were tested for their physiologies of obesity and diabetes. Mice fed with PGE showed dramatic reduced body weight. Weight of liver and fat tissue also decreased in PGE group. Furthermore, mice of PGE group showed lower fasting glucose level and improved glucose and insulin sensitivity. In order to investigate the underlying mechanism of anti-obesity and anti-diabetic effect of PGE, the livers were isolated and hepatic proteome was examined by LC-MS/MS. Comparison of protein expression profiles revealed that changes of protein expression in HFD mostly reverted to normal state by intaking PGE. The proteins were mainly involved in lipid metabolism, fatty acid β-oxidation, oxidative phosphorylation, energy production, and mitochondrial dysfunction. Interestingly, proteins associated with epithelial adherents junction signaling are also regulated by PGE in the rescue process of type 2 diabetes.