The treatment of repeatedly recurrent carcinoma of the floor of the mouth (FOM) is challenging. There is no standard strategy for such patients with poor physical condition after multiple lines of treatment. Angiogenesis is a key in tumor initiation, growth, and dissemination. Apatinib, a potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), has been approved for the treatment of late-stage gastric or gastroesophageal junction adenocarcinoma that is resistant to at least two lines of chemotherapy. Its application in intractable FOM squamous carcinoma has never been described before. Herein, we present the case of a heavily treated patient with FOM squamous carcinoma undergoing a third local relapse in the right region of the neck and anterior cervical region. Oral apatinib was administered daily at a dose of 250 mg. There was clear and rapid efficacy that led to complete remission. However, giant, deep ulcers formed due to tumor necrosis. The patient eventually died of massive bleeding resulting from the major cervical vascular rupture caused by tumor necrosis and erosion. This case is novel and instructional, highlighting that apatinib might be effective, with manageable toxicity, for certain patients with refractory head and neck squamous cell carcinoma (HNSCC). The advantages and disadvantages of apatinib should be carefully evaluated, and close surveillance and quick intervention as required are critical to reduce fatal cancer-associated complications. The role of apatinib in recurrent or metastatic HNSCC needs to be clarified by multicenter trials in the near future.