Head and neck squamous cell carcinoma (HNSCC) is extremely challenged to undergo sNurgeries and the underlying mechanisms behind it remain unclear. We evaluated whether DDX5 functions indispensably in HNSCC prognosis and found that DDX5 is up-regulated among HNSCC samples and overexpression enhances HNSCC. The β-catenin signaling pathway activation with the DDX5 assistance promotes HNSCC in vitro. Targeting β-catenin signaling pathway utilizing MSAB as inhibitor successfully ameliorates HNSCC in subcutaneous injection mouse model in vivo as well as malignant functions in vitro. Our findings elucidate that DDX5 might function as an oncogenic biomarker for HNSCC, which could be a candidate target in clinical therapies.