Prune homolog 2 with BCH domain (PRUNE2) is associated with prostate cancer, neuroblastoma, glioblastoma and melanoma; however, the function of PRUNE2 in colorectal cancer (CRC) remains unknown. The present study aimed to evaluate the effects of PRUNE2 on the development of CRC. The biological function of PRUNE2 in CRC cell lines was investigated by using Cell Counting Kit-8, colony formation, flow cytometry and Transwell assay. Additionally, a mouse model was established to investigate the effect of PRUNE2 on metastasis of CRC cells. The expression levels of PRUNE2 were lower in CRC compared with adjacent normal tissue and this expression pattern was associated with poor relapse-free survival probability. PRUNE2 overexpression significantly decreased cell proliferation and invasion, increased cell apoptosis and arrested the cell cycle. Consistently, it increased the protein expression levels of pro-apoptosis genes and decreased the expression of antiapoptotic proteins. PRUNE2 knockdown had the opposite effects. Furthermore, PRUNE2 overexpression decreased the tumorigenicity of CRC cells. In conclusion, PRUNE2 decreased cell survival, proliferation, invasion and tumorigenicity and promoted apoptosis, suggesting that PRUNE2 may function as a tumor-suppressive gene in CRC.