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Liver cancer is a significant global health concern, prompting the search for innovative therapeutic solutions. <i>Yadanziolide A</i> (<i>Y-A</i>), a natural derivative of Brucea javanica, has emerged as a promising candidate for cancer treatment; however, its efficacy and underlying mechanisms in liver cancer remain incompletely understood. In this study, we conducted a comprehensive evaluation of <i>Y-A’</i>s effects on liver cancer cells using a range of in vitro assays and an orthotopic liver cancer mouse model. Our findings reveal that <i>Y-A</i> exerts dose-dependent cytotoxic effects on liver cancer cells, significantly inhibiting proliferation, migration, and invasion at concentrations ≥ 0.1 μM. Furthermore, <i>Y-A</i> induces apoptosis, as evidenced by increased apoptotic cell populations and apoptosome formation. In vivo studies confirm that <i>Y-A</i> inhibits tumor growth and reduces liver damage in mouse models. Mechanistically, <i>Y-A</i> targets the TNF-α/STAT3 pathway, inhibiting STAT3 and JAK2 phosphorylation, thereby activating apoptotic pathways and suppressing tumor cell growth. These results suggest that <i>Y-A</i> has promising anticancer activity and potential utility in liver cancer therapy.