Lymphatic metastasis (LM) remains a major contributor to mortality among patients with head and neck squamous cell carcinoma (HNSCC). Understanding the molecular mechanisms underlying LM and identifying novel therapeutic targets are critical priorities. This study investigated ADAM22, a protein implicated in cell adhesion, migration, and differentiation, for its role in HNSCC and its association with LM. Its expression levels were evaluated in HNSCC tissues with and without LM using quantitative real-time PCR (qRT-PCR), western blotting, and immunohistochemistry. The prognostic relevance of ADAM22 was analyzed through Kaplan-Meier survival curves and Cox proportional hazards models. Functional assays, including EdU incorporation, flow cytometry, wound healing, and Transwell migration assays, were performed in FADU and SCC15 cell lines alongside an in vivo footpad xenograft mouse model. ADAM22 was found to be significantly overexpressed in HNSCC cases with LM. In vitro, silencing of ADAM22 suppressed tumor cell proliferation, migration, and invasion and promoted apoptosis. Both in vitro and in vivo experiments demonstrated that ADAM22 enhances tumor growth and lymphatic spread by promoting epithelial-mesenchymal transition (EMT). Further analysis identified integrins as key mediators in ADAM22-driven EMT and metastasis. In summary, these findings indicate that ADAM22 promotes LM in HNSCC by regulating EMT through integrin signaling, highlighting its potential as a therapeutic target and providing new perspectives for diagnosing and treating HNSCC.