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Background: Hepatocellular carcinoma (HCC) presents a challenging global health concern due to its high incidence and limited treatment efficacy. Understanding the molecular pathways driving HCC development is crucial for advancing therapeutic strategies and improving patient outcomes., Objective: This study aims to assess the impact of Salinomycin on the Wnt/β-catenin signaling pathway in hepatocellular carcinoma, exploring its role in tumor migration and angiogenesis. Additionally, to explore the therapeutic potential of targeting this pathway for improving HCC treatment outcomes., Methods: This study employed an in vitro experimental design to investigate the role of the Wnt/β-catenin signaling pathway in HCC progression. HepG2 cells were cultured in RPMI 1640 medium supplemented with 10% serum, penicillin (100 U/ml), and streptomycin (100 μg/ml). The cells were divided into experimental and control groups for comparative analysis. Salinomycin was administered to inhibit Wnt/β-catenin pathway activation. The primary outcome measures included the evaluation of cell migration and tumor angiogenesis using cell migration assays and vascular endothelial growth factor (VEGF) expression analysis, respectively. Statistical analysis was performed using the two-tailed Student's t test, with significance set at P < .05., Results: Salinomycin treatment led to a dose-dependent decrease in HCC cell proliferation, with optical density values decreasing as the concentration of Salinomycin increased. Cell migration assays showed inhibited migration in cells treated with Salinomycin compared to controls. Western blot analysis revealed decreased levels of β-catenin and increased levels of DVL in Salinomycin-treated cells, indicating inhibition of the Wnt/β-catenin pathway. Furthermore, VEGF expression decreased after Salinomycin treatment, implicating the pathway in tumor angiogenesis. Statistical analysis, including Student's t-test, confirmed significant differences between control and experimental groups (P < .05)., Conclusion: The Wnt/β-catenin signaling pathway plays a significant role in the migration and angiogenesis of HCC when treated with Salinomycin.