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(<b>Purpose</b>) Previous studies have pointed out the significance of IgG Fc binding protein (FCGBP) in carcinogenesis, cancer progression, and tumor immunity in certain malignancies. However, its prognostic values, molecular interaction, and immune characteristics in the head and neck squamous cell carcinoma (HNSC) remained unclear. (<b>Methods</b>) To evaluate the potential role of the <i>FCGBP</i> gene, we used GEPIA2 and UALCAN platforms to explore the differential levels, survivals, and genetic alteration through cBioPortal (based on The Cancer Genome Atlas dataset). STRING, GeneMania, and TIMER2.0 identified the interacting networks. LinkedOmics performed Gene enrichment analysis, and TISIDB and TIMER2.0 evaluated the role of <i>FCGBP</i> in the tumor microenvironment. (<b>Results</b>) The expression level of <i>FCGBP</i> is lower in cancer tissues. A high <i>FCGBP</i> level is significantly associated with better overall- and disease-specific-survivals, regardless of human papillomavirus infection. Low <i>FCGBP</i> levels correlated to a higher <i>tumor protein p53</i> (<i>TP53)</i> mutation rate (<i>p</i> = 0.018). <i>FCGBP</i> alteration significantly co-occurred with that of <i>TP53</i> (<i>q =</i> 0.037). Interacting networks revealed a significant association between FGFBP and trefoil factor 3 (TFF3), a novel prognostic marker in various cancers, at transcriptional and translational levels. Enrichment analyses identified that the top gene sets predominantly related to immune and inflammatory responses. Further investigation found that the <i>FCGBP</i> mRNA level positively correlated to the infiltration rates of B cells, Th17/CD8+ T lymphocytes, T helper follicular cells, mast cells, and expression levels of various immune molecules and immune checkpoints in HNSC. (<b>Conclusions</b>) We found that the <i>FCGBP</i> mRNA level negatively correlated to <i>TP53</i> mutation status while positively correlated to the <i>TFF3</i> level. Additionally, FCGBP may regulate the tumor microenvironment. These findings support the <i>FCGBP</i> as a potential biomarker to estimate HNSC prognoses.