Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors, often with a poor prognosis. The HBx protein, encoded by the hepatitis B virus (HBv), is significantly associated with the pathogenesis of HCC. Although studies suggested that the von Willebrand factor (vWF) is key to the progression of HCC associated with HBv, the underlying mechanisms are largely obscure. Here we report that high vWF expression predicts poor prognosis in HCC patients infected with HBv. In vitro studies have shown that vWF enhances the migration, invasion, proliferation, and epithelial-mesenchymal transition (EMT) of HCC associated with HBv, and also inhibits apoptosis. We demonstrated that HBv-encoded oncogene X protein (HBx), a core protein of HBv expression can facilitate the transcription of vWF through the upregulation of ASCL1. Furthermore, miR-3150b-3p, which is negatively regulated by HBx, was screened to bind to the 3'UTR of ASCL1 and mediate ASCL1 silencing. Finally, we found that ST8SIA6-AS1 is positively regulated by HBx, which could sponge miR-3150b-3p, consequently impacting the expression of ASCL1 and ultimately alters the protein levels of vWF. In conclusion, our study identified that Hepatitis B Virus X Protein affected vWF level in HBv-related HCC through ST8SIA6-AS1/miR-3150b-3p/ASCL1 axis, which in turn promoted tumor malignant progression.