The objective of this research was to create a prognostic model focused on genes related to ubiquitination (UbRGs) for evaluating their clinical significance in head and neck squamous cell carcinoma (HNSCC) patients. The transcriptome expression data of UbRGs were obtained from The Cancer Genome Atlas (TCGA) database, and weighted gene co-expression network analysis (WGCNA) was used to identify specific UbRGs within survival-related hub modules. A multi-gene signature was formulated using LASSO Cox regression analysis. Furthermore, various analyses, including time-related receiver operating characteristics (ROCs), Kaplan–Meier, Cox regression, nomogram prediction, gene set enrichment, co-expression, immune, tumor mutation burden (TMB), and drug sensitivity, were conducted. Ultimately, a prognostic signature consisting of 11 gene pairs for HNSCC was established. The Kaplan–Meier curves indicated significantly improved overall survival (OS) in the low-risk group compared to the high-risk group (p < 0.001), suggesting its potential as an independent and dependable prognostic factor. Additionally, a nomogram with AUC values of 0.744, 0.852, and 0.861 at 1-, 3-, and 5-year intervals was developed. Infiltration of M2 macrophages was higher in the high-risk group, and the TMB was notably elevated compared to the low-risk group. Several chemotherapy drugs targeting UbRGs were recommended for low-risk and high-risk patients, respectively. The prognostic signature derived from UbRGs can effectively predict prognosis and provide new personalized therapeutic targets for HNSCC.