The chemokine receptor CXCR7 has been suggested to play important roles in the progression of several types of cancers. However, few studies have investigated the biological roles of CXCR7 in head and neck squamous cell carcinoma (HNSCC). CXCR7 expression and its clinical implications were examined in 103 HNSCC tissues using immunohistochemistry (IHC). The biological roles and mechanisms of CXCR7-mediated signaling pathways were investigated in HNSCC cells through CXCR7 overexpression in vitro and in vivo. High expression of CXCR7 was significantly associated with tumor size (P = 0.007), lymph node metastasis (P = 0.004), and stage (P = 0.020) in HNSCC. Overexpression of CXCR7 in HNSCC cells enhanced cell migration and invasion in vitro and promoted lymph node metastasis in vivo. CXCR7 also induced epithelial-mesenchymal transition through PI3K/AKT. CXCR7 increased secretion of transforming growth factor-β1 (TGF-β1) and promoted EMT through phosphorylated Smad2/3. Taken together, our results provide functional and mechanistic roles of CXCR7 as a master regulator of oncogenic TGF-β1/Smad2/3 signaling in HNSCC, suggesting that CXCR7 might be a therapeutic target for the treatment of HNSCC.