Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy in the world; oral squamous cell carcinomas (OSCC) account for the majority of HNSCC cases. A major driver of OSCC is the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK) with 12 N-glycosylation sites whose activity is aberrantly upregulated in 80-90% of tumors. EGFR antennary-fucosylated glycans have been shown to suppress EGFR dimerization and signaling in lung adenocarcinoma. High levels of fucosylated glycan epitopes have also been observed in OSCC, but invasive regions lose expression of linkage-specific fucosylated epitopes, suggesting that certain fucosylated glycans are involved in the suppression of cell growth and invasion. We found that EGFR from metastatic HSC-3 cells has low levels of fucosylated N-glycans, while EGFR from non-metastatic CAL27 cells shows higher levels of fucosylation at multiple EGFR glycosylation sites including sites N420 and N579, via nUPLC-MS/MS. In cell culture and in mouse tumor xenografts, treatment with ICG-001, a small molecule inhibitor of the interaction between nuclear -catenin and CREB-binding protein (CBP) resulted in higher expression of FUT2 and FUT3, higher fucosylation of EGFR at sites N420 and N579, and decreased EGFR abundance. In addition, we have performed in-depth characterization of multiply-fucosylated N-glycans via glycopeptide tandem mass spectrometry to understand which fucosylated glycan epitopes are involved in the observed effect.