Colorectal cancer (CRC) currently leads to many deaths worldwide. The regulatory mechanism, however, remains largely unclear. In the present study, bioinformatics methods were used to identify genes associated with CRC prognosis and to detect the molecular signals regulating the cell cycle in two CRC cell lines. It was revealed that BNIPL‑2 expression was higher in CRC tissues than in adjacent tissue samples. Upregulation of BNIPL‑2 was correlated with poor prognosis and the adverse malignant stages T and M. BNIPL‑2 was also associated with signaling pathways involved in cancer cell growth. BNIPL‑2 overexpression promoted cell proliferation and increased the proportion of cells in the G2/M phase. Knockdown of BNIPL‑2 inhibited cell proliferation. CD44 was regulated by BNIPL‑2 and promoted cell proliferation. Downregulation of CD44 suppressed cell proliferation and rescued the cell proliferation promoted by BNIPL‑2. Overexpression of CD44 restored the cell proliferation suppressed by BNIPL‑2 knockdown. The present study not only suggested that BNIPL‑2 may be a potential biomarker of CRC but also indicated that BNIPL‑2 regulates CRC cancer proliferation via CD44, which could be a diagnostic and clinical treatment target.