Abstract: Head and Neck Squamous Cell Carcinoma (HNSCC) is characterized by high malignancy and poor prognosis. The emergence of anti-tumor targeted therapy and immunotherapy has provided new hope for HNSCC patients. This article outlines recent advances in the research background, mechanisms of action, and biological functions of the therapeutic targets EGFR (Epidermal Growth Factor Receptor) and PD-1/PD-L1 (Programmed Death-1/Programmed Death-Ligand 1) in HNSCC. It particularly focuses on the current clinical status of these two key targets and examines the preclinical rationale and clinical trial results of their corresponding combination strategies. Future research could explore personalized treatment regimens for HNSCC patients and identify reliable biomarkers capable of predicting treatment response, with the aim of achieving individualized precision medicine for HNSCC.