Background and Purpose: Ginsenosides, bioactive compounds from Panax ginseng, exhibit anticancer properties. Regorafenib, a multikinase inhibitor, is utilized as a second-line therapy for advanced hepatocellular carcinoma (HCC), offering modest survival benefit. This study aimed to investigate the activity of selectively screened ginsenosides and the mechanisms underlying their effects on HCC cells in combination with regorafenib. Experimental Approach: The synergistic effects and optimal drugs concentrations were analyzed using SynergyFinder 2.0. A phosphokinase activity assay was conducted to elucidate the fundamental mechanisms modulated by the combined treatment in vitro, and our findings were validated in vivo xenograft model. Key Results: From the ginsenosides screening, Rh3 significantly enhanced apoptosis and sensitized HCC cells to regorafenib. Phosphokinase activity assay revealed that this effect was associated with the inhibition of signal transducer and activator of transcription 3 (STAT3), regulated by the Janus kinase pathway, and led to the suppression of TEAD promoter activity without causing yes-associated protein (YAP) nuclear translocation. The combination treatment also suppressed tumor growth in the xenograft model. Conclusion and Implications: This study is the first to propose that regorafenib and ginsenoside Rh3 synergistically enhances apoptosis in HCC by targeting JAK/STAT and YAP-TEAD signaling. These findings suggest a promising therapeutic approach for HCC, warranting further clinical investigation.