There is an urgent need for effective molecular therapies for hepatocellular carcinoma (HCC), the third-leading cause of cancer-related deaths worldwide. Norcantharidin (NCTD), a demethylated derivative of cantharidin, reportedly exhibits anticancer activity against various types of tumors, including HCC, though the mechanisms involved remain largely unknown. Here, we report that NCTD reduces viability of human MHCC-97H (97H) and HepG2 HCC cells, and induces cell death by triggering high levels of autophagy. Moreover, a significant attenuation of tumor growth was observed after NCTD treatment of HepG2 tumors in vivo, and this effect was enhanced by co-treatment with the c-Met inhibitor crizotinib. Interestingly, western blot analyses showed that the cytotoxic autophagy induced by NCTD correlates with a reduction in the phosphorylation status of both c-Met and m-TOR. These results suggest that cytotoxic autophagy resulting from inhibition of c-Met/mTOR signaling may be achieved in HCC by combined NCTD and crizotinib administration. Further studies to validate the therapeutic potential of this approach are warranted.