The importance of energy metabolism in cancer was explored by accumulating studies. Energy metabolism can affect the cellular activities of tumors. However, there is few research exploring the role of energy metabolism in tumor immune microenvironment. In this context, we constructed a novel energy metabolism-related prognostic signature containing 8 genes. The risk score calculated by the signature was analyzed to be an independent value of head and neck squamous cell carcinoma (HNSCC). We further validated the effectiveness and accuracy of our signature in The Cancer Genome Atlas Program (TCGA) cohort and Gene Expression Omnibus (GEO) cohort. Moreover, we also revealed a negative correlation between the risk score and the activity of the immune processes. Finally, we validated the function of Desmoglein 2 protein (DSG2), a risk gene in the signature, in tumor progression and found that knockdown of DSG2 remarkably suppressed the proliferation and migration of HNSCC cells, which further validated our analysis. In conclusion, the energy metabolism-related gene signature we built is a prospective biomarker of HNSCC, which can offer valuable clues for the research and development of immunotherapeutic drugs in HNSCC.