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Hepatocellular carcinoma (HCC) remains a major global health burden, characterized by limited therapeutic options and poor prognosis. The present study aimed to evaluate the anticancer potential of leonurine, a natural alkaloid derived from Leonurus japonicus, in HCC. Through an integrated approach of network pharmacology and experimental validation, the PI3K/AKT signaling pathway was identified as a key therapeutic target of leonurine. In vitro experiments demonstrated that leonurine dose‑dependently inhibited HCC cell proliferation, migration and invasion by suppressing PI3K/AKT activation and reversing epithelial‑mesenchymal transition (EMT). In vivo studies confirmed that leonurine significantly attenuated tumor growth and metastasis, with synergistic antitumor effects observed when combined with the PI3K inhibitor LY294002. Collectively, these findings highlight leonurine as a promising candidate for HCC treatment, exerting its efficacy through PI3K/AKT pathway modulation and EMT inhibition. Moreover, the results provide a solid foundation for future clinical investigations and the development of leonurine‑based combination therapies to improve HCC treatment outcomes.