Abstract: Head and neck squamous cell carcinoma (HNSCC) is a common malignant tumor with a relatively high degree of malignancy, which often induces recurrence and metastasis. Epidermal growth factor receptor (EGFR) is an important oncogene that is overexpressed in HNSCC and is negatively correlated with prognosis, making it an important therapeutic target. However, EGFR-targeted therapy for HNSCC is not as effective as it is for non-small cell lung cancer. Recent studies have found that EGFR can promote resistance of tumor cells to therapeutic agents via its overexpression, mutation, single nucleotide polymorphism, nuclear translocation, and induction of autophagy. This article will review these aspects and discuss how to utilize EGFR more effectively in treating HNSCC, and also provide a new direction for exploring therapeutic strategies for HNSCC.