Sauchinone is a pharmacologically active compound isolated from Saururus chinensis, which has been used as a traditional Oriental medicine to treat fever, jaundice, and various inflammatory diseases. In this study, we investigated the effect of sauchinone against hepatocellular carcinoma (HCC) and sought to elucidate the mechanism involved. Cell viability was measured by an MTT assay. Cell cycle distributions and the mitochondrial membrane potential were analyzed using flow cytometry. Cell death was analyzed by annexin V assay, 4',6-diamidino-2-phenylindole staining, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Protein and mRNA levels were assessed by western blot and real-time PCR, respectively. Malignant properties were investigated by a wound healing migration assay and invasion assay. Sauchinone suppressed the proliferation of human HCC cells in a dose-dependent manner. Moreover, it induced the G0/G1 phase cell cycle arrest and mitochondrial dysfunction and then triggered the apoptosis by activating the JNK/p38 pathway in Huh-7 cells. In addition, sauchinone induced the activation of the AMP-activated protein kinase (AMPK) pathway, and compound C (an AMPK inhibitor) blocked the sauchinone-induced mitochondrial dysfunction. The AMPK activation by sauchinone inhibited the phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream targets, such as ribosomal protein S6 kinase 1 and eIF4E-binding protein 1. Furthermore, sauchinone attenuated key proangiogenic factors, including hypoxia-inducible factor-1α, vascular endothelial growth factor, and plasminogen activator inhibitor-1, resulting in decreased migration and invasion of HCC cells. These results provide evidence for sauchinone to be considered as a potent anticancer agent by targeting of the AMPK-mTOR pathway in HCC.