Head and neck squamous cell carcinomas (HNSCCs) are derived from the mucosal linings of the upper aerodigestive tract, salivary glands, thyroid, oropharynx, larynx, and hypopharynx. The present study aimed to identify the novel genes and pathways underlying HNSCC. Despite the advances in HNSCC research, diagnosis, and treatment, its incidence continues to rise, and the mortality of advanced HNSCC is expected to increase by 50%. Therefore, there is an urgent need for effective biomarkers to predict HNSCC patients' prognosis and provide guidance to the personalized treatment. Both HNSCC clinical and gene expression data were abstracted from The Cancer Genome Atlas (TCGA) database. Intersecting analysis was adopted between the gene expression matrix of HNSCC patients from TCGA database to extract TME-related genes. Differential gene expression analysis between HNSCC tissue samples and normal tissue samples was performed by R software. Then, HNSCC patients were categorized into clusters 1 and 2 via NMF. Next, TME-related prognosis genes ( < 0.05) were analyzed by univariate Cox regression analysis, LASSO Cox regression analysis, and multivariate Cox regression analysis. Finally, nine genes were selected to construct a prognostic risk model and a prognostic gene signature. We also established a nomogram using relevant clinical parameters and a risk score. The Kaplan-Meier curve, survival analysis, time-dependent receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and the concordance index (C-index) were carried out to assess the accuracy of the prognostic risk model and nomogram. Potential molecular mechanisms were revealed by gene set enrichment analysis (GSEA). Additionally, gene correlation analysis and immune cell correlation analysis were conducted for further enriching our results. A novel HNSCC prognostic model was established based on the nine genes (GTSE1, LRRN4CL, CRYAB, SHOX2, ASNS, KRT23, ANGPT2, HOXA9, and CARD11). The value of area under the ROC curves (AUCs) (0.769, 0.841, and 0.816) in TCGA whole set showed that the model effectively predicted the 1-, 3-, and 5-year overall survival (OS). Results of the Cox regression assessment confirmed the nine-gene signature as a reliable independent prognostic factor in HNSCC patients. The prognostic nomogram developed using multivariate Cox regression analysis showed a superior C-index over other clinical signatures. Also, the calibration curve had a high level of concordance between estimated OS and the observed OS. This showed that its clinical net can precisely estimate the one-, three-, and five-year OS in HNSCC patients. The gene set enrichment analysis (GSEA) to some extent revealed the immune- and tumor-linked cascades. In conclusion, the TME-related nine-gene signature and nomogram can effectively improve the estimation of prognosis in patients with HNSCC.