Accumulating evidences have shown that unfolded protein response (UPR) contributes to the increased survival of tumor cells under endoplasmic reticulum (ER) stress conditions. Malectin is an ER-resident lectin that selectively traps misfolded glycoproteins in ER for degradation, and its expression is upregulated upon ER stress. However, contribution of malectin to malignant behavior of tumor has not been reported. Here, we revealed that malectin expression is aberrantly up-regulated in human hepatocellular carcinoma (HCC) tissues and HCC cell lines compared to their matched normal tissues and cell lines. Knockout of malectin in two HCC cell lines HepG2 and QGY-7703 using CRISPR-Cas9 technology had no obvious effects on cell proliferation, but significantly suppressed cell colony formation, migration and invasion. Consistently, subcutaneously implanted malectin-deficient HCC cells in nude mice also showed an obvious decrease in tumor growth. These results indicate that malectin might play an oncogenic role in HCC tumorigenesis and development.