Objective To investigate the effects of ponatinib (a multi-target kinase inhibitor) on the proliferation of SNU-449 human hepatocellular cancer cells and the underlying mechanism. Methods SNU-449 hepatocellular cancer cells were treated with 16 tyrosine kinase inhibitors for 72 hours. Then MTT assay was used to detect the effects of ponatinib on the survival and proliferation of the cancer cells. Ponatinib was the most sensitive drug to SNU-449 cells and the IC50 value was obtained. SNU-449 cells were cultured and treated with (0.06, 0.3, 0.6) μmol/L ponatinib, and the control group was treated with DMSO. Colony formation assay and inverted microscope were applied to observe the effects of ponatinib on the colony formation ability and morphology of SNU-449 cells. Flow cytometry was used to detect the effects of ponatinib on the apoptosis and cell cycle of SNU-449 cells. Western blotting was performed to examine the expression of Src, phosphorylated Src (p-Src), mitogen-activated protein kinase kinase (MEK), phosphorylated MEK (p-MEK), extracellular signal-regulated kinase (ERK), phosphorylated ERK (p-ERK), phosphoinositide 3-kinase (PI3K), phosphorylated PI3K (p-PI3K), phosphoinositide-dependent protein kinase 1 (PDK1), phosphorylated PDK1 (p-PDK1), AKT, p-AKT, mammalian target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR). Results MTT assay showed that ponatinib displayed the best inhibitory effects on SNU-449 cells in 16 tyrosine kinase inhibitors. Ponatinib promoted cell apoptosis in a concentration-dependent manner and induced cell cycle arrest at the G1 phase in SNU-449 cells. A number of kinase signaling pathways were inhibited by ponatinib, including the Src signaling pathway, MAPK pathway and PDK1/AKT/mTOR pathway. Conclusion Ponatinib can inhibit the proliferation, promote the apoptosis and cell cycle arrest of hepatocellular cancer cells and block MAPK and PDK1/AKT/mTOR signaling pathways, which might be a potential agent for liver cancer treatment.