An antimalarial medication, artesunate (Art), has exhibited promising anticancer effects with excellent tolerability in various types of cancer, suggesting that it has the potential to be used in combination with sorafenib (Sora) in hepatocellular carcinoma (HCC) treatment. To determine the potency of this combination, the present study attempted to quantitatively measure the dose-effect relationship of each drug alone and in combination in liver cancer cells in vitro using Calcusyn software. Cell growth inhibition was determined using the CyQUANT proliferation assay in two liver cancer cell lines, HepG2 and Huh7. Drug combination and reduction indices and isobologram plots were used to assess drug interactions. Cell apoptosis was evaluated by measurements of the proportion of cells in the sub G 0/G 1 phase of the cell cycle, and determination of protein expression levels of cleaved poly ADP ribose polymerase and caspase-9. Additionally, a cell migration assay was conducted using Essen ImageLock plates with an IncuCyte Zoom imaging system. The results of the present study revealed that the inhibitory effect of Sora on cell growth was synergistically enhanced by the combination with Art in HepG2 and Huh7 cells. The combination index and dose reduction index were specific to each cell line. Furthermore, combination at a fixed ratio presented mutual enhancement with respect to apoptosis induction and suppression of in vitro liver cancer cell migration. Therefore, considering the low toxicity and well-defined clinical characteristics of Art, combination of Sora and Art may present an attractive therapeutic option in the development of clinical trials for HCC treatment.