Sorafenib is the FDA-approved first-line target drug for HCC patients. However, sorafenib only confers 3-5 months of survival benefit with <30% of HCC patients. Thus, it is necessary to develop a sensitizer for hepatocellular carcinoma (HCC) to sorafenib. Here, we report that in representative HCC cell lines (SMMC-7721 and PLC8024) that are insensitive to sorafenib, 3-HAA (50<mu>M) significantly enhances cell sensitivity to sorafenib to an extent that could not be explained by additive effects. In nude mice carrying HCC xenograft, tumor growth is inhibited by sorafenib (10mg/kg/day) or 3-HAA (100mg/kg/day) alone. When used in combination, the treatment effectively prevents the xenograft from growing. In a set of mechanistic experiments, we find enhanced AKT activation and increased proportion of CD44(+)CD133(+) cells in sorafenib-resistant HCC cells and tissues. The proportion of CD44(+)CD133(+) cells is reduced upon 3-HAA treatment in both cultured cells and mouse xenografts, suggesting that 3-HAA could decrease the stemness of HCC. We also detect decreased phosphorylation of AKT, a regulator of the GSK3 beta/beta -catenin signaling upon 3-HAA treatment. The AKT activator SC79 activates GSK3 beta/beta -catenin signaling while the Wnt inhibitor XAV-939 abolishes 3-HAA inhibition of HCC growth in vitro and in mice. The current study demonstrates that 3-HAA sensitizes HCC cells to sorafenib by reducing tumor stemness, suggesting it is a promising molecule for HCC therapy.