There are no effective therapeutic options for locally advanced head and neck squamous cell carcinoma (HNSCC). Additionally, there is no standard therapy for patients subjected to multiple lines of treatment. Angiogenesis plays a key role in tumor growth and metastasis. Therefore, inhibition of tumor angiogenesis is an important strategy for tumor therapy. Apatinib is a novel tyrosine kinase inhibitor that inhibits angiogenesis by targeting vascular endothelial growth factor receptor-2 (VEGFR-2). The effect of apatinib on HNSCC has not been clearly established. In this study, we administered apatinib in combination with anti-epidermal growth factor receptor (EGFR) targeted and systemic chemotherapy for the treatment of oral cancer and to achieve better disease outcomes. To avoid fatal bleeding, after achieving good clinical outcomes, the follow-up treatment plan was adjusted. The efficacy of apatinib combined with anti-EGFR targeted and systemic chemotherapy for the treatment of oral cancer has not been previously reported. Our findings show the therapeutic potential of apatinib for advanced HNSCC patients with multiple lines of chemotherapy, especially for patients with large neck masses.