Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer globally and presents a persistent clinical challenge due to the limited availability of effective targeted therapeutics. Recent studies have identified the ubiquitin-associated and SH3 domain-containing B (UBASH3B), a tyrosine phosphatase, as a key oncogenic player in HNSCC pathogenesis. Elevated UBASH3B expression correlates with poor clinical outcomes in HNSCC patients. Mechanistically, UBASH3B promotes tumor progression by stabilizing the epidermal growth factor receptor (EGFR) levels, thereby enhancing downstream signaling pathways that promote cancer cell proliferation, survival, and therapeutic resistance. In this review, we provide a comprehensive overview of the structural features and physiological functions of UBASH3B, along with a focused discussion on its emerging role in HNSCC tumorigenesis. We further explore the potential of targeting UBASH3B as a novel therapeutic target, underscoring its promise in reshaping treatment paradigms. Elucidating the molecular functions of UBASH3B in HNSCC may uncover new vulnerabilities and pave the way for the development of novel therapeutic strategies that target its activity.