The effect of a novel semi-natural derivative of naringenin, 6-C-(E-phenylethenyl)naringenin (6-CEPN) on hepatocellular carcinoma (HCC) stemness was evaluated both in vitro and in vivo. 6-CEPN reduced HCC cell viability, inhibited sphere formation, cell migration and invasion, and blocked epithelial-mesenchymal transition. It was equally effective against NANOG+ cells sorted from cultured HCC cells that was accompanied by downregulation of stemness-associated transcription factors and attenuated HIF-1 activity. Furthermore, 6-CEPN significantly enhanced the sensitivity of HCC cells to therapeutic drugs, and inhibited HCC tumor growth and lung metastasis of HCC cells. 6-CEPN suppressed Wnt/β-catenin signaling by inducing β-catenin degradation and inhibiting its nuclear translocation. Upregulation of GSK3β appeared to be crucial for 6-CEPN's inhibitory activity in the signaling pathway. These findings indicate that 6-CEPN has a strong effect against liver cancer, which is mediated, at least in part, by suppressing the stemness of HCC cells through an action mechanism involving Wnt/β-catenin signaling.