Colorectal cancer (CRC) is one of the most prevalent malignant solid cancers worldwide involving the dysregulation of multiple signaling molecules. However, the role and corresponding mechanism of basic leucine zipper and W2 domains 2 (BZW2) in CRC development, to our knowledge, has not been reported. We found BZW2 was overexpressed in human CRC tissues compared with that in paired adjacent colorectal samples. BZW2 overexpression was closely associated with tumor T stage (p = .030), metastatic lymph nodes (p = .037), TNM stage (p = .018) and the worse prognosis of CRC patients (p = .009). Moreover, BZW2 was an independent disadvantage prognostic factor (p = .031). BZW2 also showed an increased expression in different invasive CRC cell lines. Its silencing and overexpression diminished and increased cell proliferation, invasion, and migration in Colo205 and HCT116 cells via specifically activating of extracellular-signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signaling. Moreover, ERK/MAPK inhibitor PD98059 reverse the enhancement of cell proliferation, invasion, and migration in BZW2 overexpressing HCT116 cells. BZW2 silencing also inhibited subcutaneous tumors growth and p-ERK expression in vivo. BZW2 promotes the malignant progression of CRC via activating ERK/MAPK signaling, which provided a promising gene target therapy for CRC.