Despite significant breakthroughs in frontline cancer research and chemotherapy for hepatocellular carcinoma (HCC), many of the suggested drugs have high toxic side effects and resistance, limiting their clinical utility. Exploring potential therapeutic targets or novel combinations with fewer side effects is therefore crucial in combating this dreadful disease. The current study aims to use a novel combination of ponatinib and gossypol against the HepG2 cell line. Cell survival, FGF19/FGFR4, apoptotic and autophagic cell death, and synergistic drug interactions were assessed in response to increasing concentrations of ponatinib and/or gossypol treatment. Research revealed that ponatinib (1.25-40 μM) and gossypol (2.5-80 μM) reduced the viability of HepG2 cells in a way that was dependent on both time and dose. Ponatinib's anti-proliferation effectiveness was improved synergistically by gossypol and was associated with a rise in apoptotic cell death, cell cycle blockage during the G0/G1 phase, and suppression of the FGF19/FGFR4 axis. Furthermore, the ponatinib/gossypol combination lowered Bcl-2 and p-Akt while increasing active caspase-3, Beclin-1, p62, and LC3II. This combination, however, had no harm on normal hepatocytes. Overall, gossypol enhanced ponatinib's anticancer effects in HCC cells. Notably, this new combination appears to be potential adjuvant targeted chemotherapy, a discovery that warrants more clinical investigation, in the management of patients with HCC.