Liver cancer is a gastrointestinal malignant tumor with high lethality. The prognosis of liver cancer remains poor. Compounds derived from natural products have been confirmed to alleviate the progression of various diseases, including cancers. Additionally, 6-Shogaol has been reported to induce apoptosis in liver cancer cells. However, the mechanism by which 6-shogaol regulates apoptosis in liver cancer cells remains unclear. To investigate the function of 6-shogaol in liver cancer, RT-qPCR and western blotting were used to detect the expression of TLR4 and FOXO3a in liver cancer cells, respectively. The OD value of liver cancer cells was measured using the MTT assay. Flow cytometry was used to measure cell apoptosis. 6-Shogaol inhibited the growth of liver cancer cells. TLR4 and Wnt/[Formula: see text]-catenin were upregulated in liver cancer cells, and FOXO3a was inactivated, but 6-Shogaol reversed the expression of TLR4, Wnt/[Formula: see text]-catenin and FOXO3a in liver cancer cells. Additionally, TLR4 overexpression partially reversed the inhibitory effect of 6-shogaol on the progression of liver cancer cells via Wnt/[Formula: see text]-catenin signaling. Furthermore, the 6-shogaol-induced increase in FOXO3a expression in liver cancer was notably suppressed by TLR4 or Wnt/[Formula: see text]-catenin upregulation. Thus, 6-Shogaol suppresses the progression of liver cancer by mediating Wnt/[Formula: see text]-catenin signaling and is a potential agent for the treatment of liver cancer.