Cancer cells prefers to rely on aerobic glycolysis than pyruvate oxidation to meet the high demand of energy for rapidly proliferation. Peroxisome proliferator-activated receptors (PPARs) are a kind of important ligand-inducible transcription factors and play crucial roles in glucose and lipid metabolism. Careful designing of novel agonists for PPARs, may show improvement with the side effects and also increase the therapeutic value for cancer and other metabolic disorder diseases. Compared with normal human liver cells, lower expression or acitivity of PPARs is observed in hepatocellular carcinoma (HCC). In this study, we show that oroxyloside (OAG) is a new dual agonist of PPARγ/ɑ, and inhibits cell proliferation of HCC based on metabolic switch. Via both PPAR-dependent and PPAR-independent regulations on glycolipid metabolic enzymes, OAG shuts down the catabolism of glucose and promotes fatty acids oxidation to generate acetyl-CoA for TCA cycle and oxidative phosphorylation. The metabolic switch induced by OAG results in a marked increase of reactive oxygen species (ROS) levels, leading to rapid dephosphorylation of RB and cell-cycle arrest in G1 phase. Pyruvate dehydrogenase kinase 4 (PDK4) and β-Oxidation are required for the suppression of cell cycle progression by OAG. Together, our findings provide a new drug candidate and a viable therapeutic strategy for HCC based on metabolic reprogram.