Sorafenib, a multikinase inhibitor for hepatocellular carcinoma treatment, inhibits the Raf/MAPK/ERK signaling pathway. However, PI3K/Akt signaling pathway is activated by Sorafenib and cross-talks with the Raf/MAPK/ERK signaling pathway, leading to drug resistance. 20(S)-Ginsenoside Rg3 has been reported with significant anticancer effect to numerous carcinomas by inhibition of PI3K-Akt signaling pathway. Hence, we aim to examine the synergistic anticancer activity of 20(S)-Ginsenoside Rg3 and Sorafenib via modulation of PTEN/Akt signaling pathway. Human hepatocellular carcinoma cell lines HepG2 and Huh7 were used. Cell viability, clonogenic assay, apoptosis assay, western blot analysis, xenograft treatment and immunohistochemistry were carried out. The viability of hepatocellular carcinoma cells significantly decreased by the treatment of Sorafenib combined with 20(S)-Ginsenoside Rg3, as well as the enhanced apoptotic rates. The levels of PTEN, Bax and cleaved caspase-3 expression increased, while the levels of phospho-PDK1 and phospho-Akt expression decreased by the treatment of Sorafenib combined with 20(S)-Ginsenoside Rg3. In vivo, the tumor volumes and weight decreased in the Sorafenib combined with 20(S)-Ginsenoside Rg3 group. The results demonstrated the synergistic anticancer activity of 20(S)-Ginsenoside Rg3 and Sorafenib in HCC by modulating PTEN/Akt signaling pathway. These findings suggest a promising strategy for HCC treatment, which could be performed in a sufficiently frequent manner.