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 review summarizes recent advances in the research background, mechanisms of action, and biological functions of the epidermal growth factor receptor (EGFR), a target for targeted therapy, and the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis, a target for immunotherapy, in HNSCC. It focuses on the current clinical landscape of these two pivotal targets in HNSCC management and discusses the preclinical rationale and clinical trial outcomes of emerging combination therapeutic strategies. Future investigations should aim to explore personalized treatment modalities for HNSCC patients and identify predictive biomarkers of efficacy, with the ultimate goal of achieving individualized precision medicine in the diagnosis and treatment of HNSCC.