Head and Neck Squamous Cell Carcinoma (HNSCC) exhibits significant cancer health disparities. African Americans (AAs) with HNSCC demonstrate worse overall survival compared to European Americans (EAs). While the reasons behind this disparity are multifaceted, recent findings suggest that biological features in HNSCC may contribute to differences in disease progression. We have identified the gene UBASH3B, a protein tyrosine phosphatase that plays a role in the stabilization of the Epidermal Growth Factor Receptor (EGFR). This study seeks to examine the role of UBASH3B in HNSCC and determine its impact on tumor progression. We hypothesize that the upregulation of UBASH3B in AAs contributes to the survival disparity by promoting tumor growth. An analysis using HPV-negative HNSCC The Cancer Genome Atlas (TCGA) patients showed overexpression of UBASH3B in tumor samples of both AA and EA patients, with high expression in AAs correlating with significantly worse survival outcomes. UBASH3B overexpression showed an association with perineural invasion and advanced T-stage among AA patients. The copy number value (CNV) of UBASH3B in HNSCC cells was assessed with qPCR and showed a positive correlation with UBASH3B expression. Additionally, in-vitro experiments demonstrated decreased cell viability and migratory capacity upon UBASH3B knockdown. UBASH3B is significantly associated with worse overall survival in HPV-negative AA-HNSCC patients and has been shown to increase cell proliferation and migration. These results indicate that UBASH3B is a critical oncogene in HNSCC. and presents a potential therapeutic target for new treatments and a biomarker for detection, enhancing our understanding of HNSCC’s racial disparities.