CXC chemokine receptor 7 (CXCR7) has been implicated in tumor development and metastasis in multiple malignancies. Yet, the function and molecular mechanisms of CXCR7 in human osteosarcoma (OS) are still unclear. The aim of the present study was to investigate the role of CXCR7 in human OS. The expression of CXCR7 was assessed by immunohistochemical assay using a tissue microarray procedure in 45 cases of OS tissues. A loss‑of-function approach was used to observe the effects of lentiviral vector-mediated CXCR7 siRNA (Lv-siCXCR7) on biological behaviors including proliferative activities and invasive potential, as indicated by MTT and Transwell assays in OS (MG-63 and U-2 OS) cells. The results showed that the expression of CXCR7 protein in OS tissues was significantly increased compared to that in adjacent non-cancerous tissues (68.9 vs. 53.3%, P=0.033), and was correlated with the distant metastasis of the tumors (P=0.004). Knockdown of CXCR7 suppressed proliferation and invasion of OS cells through decreased expression of PI3K, AKT, β-arrestin, proliferating cell nuclear antigen (PCNA), and matrix metalloproteinase-9 (MMP-9). In addition, the tumor volume in U-2 OS subcutaneous tumor models treated with Lv-siCXCR7 was significantly smaller than the tumor volume in the negative control group (P<0.01). Collectively, our findings indicate that upregulation of CXCR7 expression is correlated with distant metastasis of OS, while knockdown of CXCR7 blocks the development of OS cells through inhibition of the PI3K/AKT and β-arrestin pathways, suggesting that CXCR7 may serve as a potential therapeutic target for the treatment of cancer.