Abstract: The postoperative recurrence rate for locally advanced head and neck squamous cell carcinoma (LA HNSCC) remains over 50%. Neoadjuvant therapy, particularly regimens that incorporate immunotherapy, has emerged as a significant research focus due to its efficacy in stage reduction and enhancing organ preservation. This review highlights recent developments in neoadjuvant pharmacotherapy, radiotherapy, and combination strategies for LA HNSCC. Additionally, we discuss key biomarkers, such as human papillomavirus (HPV) status, tumor mutation burden, and liquid biopsy findings that are crucial for prognosis and treatment prediction. Future research should emphasize adaptive treatment strategies based on early response assessments, synergistic combinations such as immunotherapy with chemoradiotherapy, and comparative studies against standard treatment modalities.