Stomatin-like protein-2 (SLP-2) gene belongs to the stomatin supergene family, and previous studies have revealed up-regulated SLP-2 expression in gallbladder cancer, lung cancer, and esophageal cancer, while the role of SLP-2 in colorectal cancer (CRC) remains unclear and needs further investigation. Therefore, the expression levels of SLP-2 in CRC tissue and cell lines were tested in this study. Besides, we further explored the role of SLP-2 in CRC invasion and metastasis at molecular level via gene intervention technique. Our results demonstrated that the positive rate of SLP-2 expression in CRC tissues was higher than that in the adjacent non-cancerous tissues (P < 0.05); positive SLP-2 expression predicted poorer prognosis of CRC patients as an independent risk factor (P < 0.05). Cell activities and the capacity of migration and invasion significantly decreased after the suppression of SLP-2 in SW620 cells (P < 0.05). Furthermore, the suppression of SLP-2 in SW620 cells resulted in varieties of invasion and metastasis-related genes and Wnt/beta-catenin signal pathway (P < 0.05). The present study identified that SLP-2 may predict a poor prognosis in CRC patients as a novel marker, and SLP-2 may facilitate the migration and invasion of CRC via regulating Wnt/beta-catenin pathway activities.