Chemokine CXCL12 is an extracellular chemokine, which binds to its cell surface receptor CXCR4. High expressions of CXCR4 and CXCL12 are associated with biological malignant potential in colon cancers. We aimed to investigate the roles of the CXCR4/CXCL12 axis in activation of the Wnt/β-catenin pathway in the development of colon cancers. Using colon cancer cell line, we performed the RNA interference assay to downregulate the expression of CXCR4. Cells were exposed to CXCL12 and their growth and metastatic activity were examined. Matrix metalloproteinases (MMPs) activity were analyzed by the gelatin zymography assay. Cell migration ability was estimated by assays of scratch wound and transwell chamber. The expression of CXCR4 and molecules relevant to the Wnt/β-catenin pathway were analyzed by the western blotting and real-time PCR assays. Human colon cancer HT-29 cells identified high expression of CXCR4. HT-29 cells highly responded to CXCL12 stimulation, showing the increase of cell proliferation, invasion and migration through the Matrigeal. The secretion and activity of MMP-2 and MMP-9 were also stimulated in HT-29 cells exposure to CXCL12. However, the CXCR4 knockdown HT-29 cells did not response to CXCL12 stimulation. We suggested that the activation of the CXCR4/CXCL12 axis be blocked in the CXCR4 knockdown cells. This study indicated that one key to the role of the CXCR4/CXCL12 axis is activation of the Wnt/β-catenin pathway. Downregulation of the CXCR4/CXCL12 axis thus reduces cancer growth and metastasis. Targeted therapy utilizing the CXCR4/CXCL12 axis could be an effective strategy for treatment of colon cancers.