Currently no reliable indicators are available for predicting the clinical outcome of head and neck squamous cell carcinoma (HNSCC). This study aimed to develop a protein-based model to improve the prognosis prediction of HNSCC. The proteome data of HNSCC cohort was downloaded from The Cancer Proteome Atlas (TCPA) portal. The TCPA HNSCC cohort was randomly divided into the discovery and validation cohort. A protein-based risk signature was developed with the discovery cohort, and then verified with the validation cohort. The prognostic value of HER3_pY1289 was further determined. We have constructed a five-protein risk signature which was strongly associated with the overall survival (OS) in the discovery cohort. Similar findings were observed in the validation cohort. The protein-based risk signature was identified as an independent prognostic factor for HNSCC. A nomogram model built on the protein-based risk signature exhibited good performance for predicting OS. Our immunohistochemistry (IHC) analysis showed that higher HER3_pY1289 staining intensity was closely associated with unfavorable prognosis of HNSCC. HER3 suppression inhibited the proliferation and invasion capacity of HNSCC cells. Collectively, we have developed a protein-based risk signature for accurately predicting the prognosis of HNSCC, which might provide valuable information for optimal individualized treatment regimens.