Head and neck squamous cell carcinoma (HNSCC) is a common tumor type. At present, surgical treatment, radiotherapy and chemotherapy are the main treatments for HNSCC, but these treatments have not achieved satisfactory results. The pH-sensitive drug delivery system is an environmental stimuli-responsive drug delivery system that utilizes the stimulation of environmental pH to produce corresponding changes in physical structure or chemical properties, thereby regulating drug release. This delivery system is the focus of the research field of drug delivery systems. At present, the drugs used in the pH-sensitive drug delivery system in the treatment of HNSCC include adriamycin, taxanes, 5-fluorouracil, and cisplatin, and have shown good stability, tumor targeting, and drug release controllability in preclinical studies. This demonstrates great value in clinical transformation. At present, the pH-sensitive drug delivery system faces issues such as difficulty in particle size control, low drug loading, and possible immune response reactivity. Therefore, the pH-sensitive drug delivery system is still being improved. This article reviews the theoretical basis and research progress of the pH-sensitive drug delivery system in the treatment of HNSCC.