Head and neck squamous carcinomas (HNSC) are the seventh most common cancer around the world. Treatment options available today have considerable limitations in terms of efficacy. Identifying novel therapeutic targets for HNSC is, therefore, urgently needed. As a novel determined regulated cell death (RCD), Cuproptosis is correlated with the development, treatment response, and prognosis of various cancer. However, the potential role of Cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of HNSC remains unclear. To figure out whether TME cells and Cuproptosis could better predict prognosis, in this study, we analyzed the expression, mutation status, and other clinical information of 502 HNSC patients by dividing them into four clusters based on their CRGs and TME cell expression. Utilizing the LASSO-Cox method and bootstrap, we established Prognostic Cuproptosis and TME classifier, which were significantly associated with prognosis, pathways, clinical features, and immune cell infiltration in TME of HNSC. To go further, the subgroup Cup low/TMEhigh displayed a better prognosis than any others. Two GEO datasets demonstrated the proposed risk model's clinical applicability. Our GO enrichment analyses proved the conjoint effect of Cuproptosis and TME on tumor angiogenesis, proliferation, and so on. Single-cell analysis and Immunotherapy profile then provided a foundation for determining the molecular mechanisms. It revealed the prognostic risk score positively correlated with T cell activation and natural killer (NK) recruiting. As far as we know, this study is the first time to explore the involvement of CRGs regulation in the TME of HNSC. In a word, it is vital to use these findings to develop new therapeutic strategies.