Colorectal cancer (CRC) is one of the most commonly diagnosed tumors among human worldwide. Angiogenesis and tumor-associated macrophage (TAM) recruitment are closely associated with CRC development. Nevertheless, the mechanisms revealing CRC progression are still not fully understood. 5'-Nucleotidase domain containing 2 (NT5DC2), a member of the NT5DC family, modulates various cellular events to mediate tumor growth, and thus serves as a disgnostic biomarker. Here, we explored the potential of NT5DC2 on tumor progression in CRC. We first found that NT5DC2 expression was significantly up-regulated in CRC tissues and cell lines. CRC patients with higher NT5DC2 expression showed poor overall survival. Furthermore, CRC cell lines stably transfected with shNT5DC2 lentivirus plasmids exhibited markedly reduced cell proliferation, migration and invasion compared with the negative control group. Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGF-A) expression levels were remarkably reduced in CRC cells with NT5DC2 deletion, along with evidently reduced tube formation in the HUVECs cultured in the collected conditional medium. The expression levels of CC chemokine ligand 2 (CCL2) and its receptor CCR2 were found to be greatly down-regulated in CRC cells transfected with shNT5DC2. Moreover, NT5DC2 knockdown markedly suppressed the activation of protein kinase-B/nuclear transcription factor κB (AKT/NF-κB) signaling in CRC cells. Furthermore, we found that NT5DC2 deletion obviously reduced the TAM recruitments through suppressing CCL2/CCR2 and AKT/NF-κB signaling pathways. Intriguingly, our in vitro experiments demonstrated that VEGF reduction was necessary for shNT5DC2-inhibited cell proliferation, migration, invasion, angiogenesis and TAM recruitment. In vivo studies also confirmed that NT5DC2 knockdown effectively reduced the tumor growth and VEGF expression in a xonegraft mouse model with CRC. Lung metastasis of CRC cells was also hindered by NT5DC2 deletion in vivo. Collectively, our results indicated a previously unrecognized NT5DC2/VEGF/CCL2 axis involved in CRC development and metastasis.