Background. Head and neck squamous cell carcinomas (HNSC) are common malignant tumors with a high occurrence and poor prognosis. Tumor protein P73 (TP73) plays an integral role in a wide range of human malignancies, but its gene expression profile, prognostic value, and potential mechanisms in HNSC remain to be comprehensively explored. Objective. This research aimed to elucidate the potential relationship between TP73 and HNSC through bioinformatics analysis. Methods. The Cancer Genome Atlas (TCGA) database was queried to investigate the regulatory role of TP73 in HNSC. The survival probabilities linked to TP73 mRNA were determined via the Kaplan-Meier analysis using R packages. Subsequently, the association of TP73 with several clinical subgroups and immunological subtypes was studied using a cohort from the TCGA-HNSC. Functional analyses were used to identify the potential signaling pathways enriched by the correlated genes of TP73. The relationship between TP73 and immunological aspects, including immune cells, immune inhibitor genes, immune stimulator genes, and tumor immune microenvironment, were investigated. Results. This study showed that the protein and mRNA levels of TP73 in HNSC patients were significantly higher than those in normal tissues. Elevated TP73 expression was related to a better survival outcome in HNSC patients. The TP73 gene was an independent prognostic factor for overall survival in HNSC samples. TP73 was mainly involved in DNA replication, ribosome, apoptosis, mismatch repair, and folate biosynthesis. TP73 was found to be positively correlated with the majority of tumor infiltrating immune cells and immunoinhibitory genes in HNSC. Conclusions. Integrative bioinformatics and statistical analyses displayed that TP73 might serve as a novel marker for the diagnosis and prognosis of HNSC. TP73 modulates immune cells in the tumor microenvironment of HNSC patients, thereby bearing significance for HNSC immunotherapy.