Hepatocellular carcinoma (HCC) is the predominant type of primary liver malignancy with high rates of mortality worldwide. Most HCC tumors are inherently resistant to chemotherapy and despite the tremendous advances in cancer chemotherapy, their treatment remains quite challenging. Sorafenib, a multikinase inhibitor, has recently been approved for the treatment of advanced HCC. The present study aimed to further explore the potential cytotoxic activities of sorafenib in HepG2 cells as well as the possible underlying mechanisms. Thus, HepG2 cells were treated with different concentrations of sorafenib. The concentration that inhibited the growth of the cells by 50% was calculated from the fitted survival curves. The effect of sorafenib on cell cycle, apoptosis and proliferation was investigated. Sorafenib- induced cytotoxicity in HepG2 cells. This could be partially attributed to increased apoptosis by augmenting the level of active caspase-3. Moreover, sorafenib induced cell cycle arrest and had anti-proliferative effects by decreasing the level of p-Akt.