The major pathogenesis of metabolic syndrome is the development of insulin resistance, which promotes the elevation of blood pressure, dyslipidemia, and dysregulation of glucose metabolism. Liver is the principal regulator of glucose and lipid metabolism by controlling hepatic glucose production, glycogen storage and lipogenesis. Toona sinensis (TS) has been reported to be beneficial on health metabolic syndrome, however the effects of TS on liver metabolism is not clear. In this study, effects of TS on liver metabolism of high fat diet mice were investigated for the underlying mechanism. Mice were fed with high fat diet for 8 weeks followed by treatment of TSL-E (100 mg/kg body weight) for 4 weeks. Two-dimensional gel electrophoresis followed by mass spectrometry was carried out to identify differential expression of liver proteins. In addition, western blot were performed for validation of proteomic analysis. Up-regulated expression of genes involved in beta-oxidation (PPARalpha and ACO) was observed in liver of TSL-E treated mice. In contract, down-regulated expression of genes was involved in lipogenesis (ACC), lipids transport (L-F ABP) and decreased expression of proteins was involved in gluconeogenesis (Transaldolase, Enolase, PCK2 and Nudix). In conclusion, TS mediates its anti-metabolic syndrome potential through improvement of dyslipidemia and blood glucose by promoting beta-oxidation and inhibiting gluconeogenesis and lipogenesis.