Hepatocyte cell adhesion molecule (hepaCAM), a new type of CAM, belongs to the immunoglobulin superfamily. Recently, hepaCAM was reported to be implicated in cancer development, and many researchers investigated its biological function in the tumorigenesis of various cancers. However, what kind of role hepaCAM plays in colorectal cancer (CRC) remains unknown. In this study, we found that hepaCAM was downregulated in CRC tissues and cell lines. Overexpression of hepaCAM inhibited CRC cell proliferation, migration, and invasion in vitro. Furthermore, the tumorigenesis assay showed that increased expression of hepaCAM suppressed CRC tumor growth and metastasis in vivo. We also demonstrated that overexpression of hepaCAM reduced the protein expression levels of β-catenin, cyclin D1, and c-Myc, indicating its inhibitory effect on the Wnt/β-catenin signaling pathway. In conclusion, our study results suggest hepaCAM as a promising therapeutic target for CRC and provide a better understanding for the molecular basis of CRC progression.