Background: Oridonin is the core bioactive component of Rabdosia rubescens, a traditional Chinese herbal medicine used in the treatment of hepatoma. Sorafenib, a targeted therapeutic agent for advanced hepatocellular carcinoma (HCC), has recently been shown to exert limited clinical effects. However, few studies have focused on the synergistic effect of these two drugs on hepatocellular carcinoma. Methods: We treated different HCC cell lines with different concentrations of oridonin and sorafenib and assessed the viability by using MTT assays and examined proliferation, migration, invasion and apoptosis after cotreatment of HepG2 cells with 20 mu M oridonin and 5 mu M sorafenib via colony formation assays, Transwell assays and flow cytometry. Regulatory effects were measured by Western blotting. The in vivo synergistic effect was confirmed through xenograft tumor models, and tumor tissues were analyzed by immunohistochemistry. Results: The inhibitory effects of oridonin and sorafenib cotreatment on HCC cells were stronger than those of either drug alone. In addition, combined treatment with the two drugs synergistically inhibited epithelial-mesenchymal transition and the Akt pathway but not NF kappa B or MAPK signaling. Akt phosphorylation by SC79 reversed the inhibitory effects of the combined treatment. Synergistic inhibition was equally observed in vivo. Conclusion: Oridonin combined with sorafenib synergistically inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition and induced apoptosis by targeting the Akt pathway but not NF-kappa B or MAPK signaling.