This study is the first to demonstrate that MeCP2 recruiting CREB1 enforces HOXD3 expression by directly targeting the promoter hypermethylation sites of HOXD3 via the HB‐EGF cell signaling pathway to induce the invasion, migration, and angiogenesis of HCC in vitro and in vivo. This evidence concerns the gene CREB1 and hepatocellular carcinoma.