Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide. It is intrinsically resistant toward standard chemotherapy, making it imperative to develop novel selective chemotherapeutic agents. The Wnt/β‐catenin pathway plays critical roles in development and oncogenesis, and is dysregulated in HCC. Our study aims to evaluate the activity of 3 small molecule antagonists of the Tcf4/β‐catenin complex (PKF118‐310, PKF115‐584 and CGP049090) on HCC cell lines in vitro and in vivo. All 3 chemicals displayed dose‐dependent cytotoxicity in vitro against all 3 HCC cell lines (HepG2, Hep40 and Huh7), but were at least 10 times less cytotoxic to normal hepatocytes (from 3 donors) by using ATP assay. In HepG2 and Huh7 cells, treatment with the antagonists decreased Tcf4/β‐catenin binding capability and transcriptional activity, associated with downregulation of the endogenous Tcf4/ β‐catenin target genes c‐Myc, cyclin D1 and survivin. In HepG2 and Huh7 cells, treatment with the antagonists induced apoptosis and cell cycle arrest at the G1/S phase. All antagonists suppressed in vivo tumor growth in a HepG2 xenograft model, associated with apoptosis and reduced c‐Myc, cyclin D1 and survivin expressions. Our results suggest that these 3 antagonists of the Tcf4/β‐catenin complex are potential chemotherapeutic agents which may offer a pathway specific option for the clinical management of HCC.