Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) represents an advanced stage of the disease and frequently shows resistance to these current treatments, including platinum chemotherapy, cetuximab plus chemotherapy, and checkpoint inhibitors. EGFR overexpression and mutation are the most frequent genetic changes in patients with HNSCC. On the basis of this genetic feature, we proposed a combinatorial treatment using the EGFR tyrosine kinase inhibitor osimertinib (AZD) and arsenic trioxide (ATO) for compassionate use. The patient obtained treatment response and progression-free survival for about six months. mechanical verifications showed that ATO and AZD combination (ATO/AZD) significantly increased intracellular ROS levels and DNA damage. Additionally, ATO/AZD decreases the expression and activity of breast cancer type 1 susceptibility protein (BRCA1) and polo-like kinase 1 (PLK1), thereby impairing Rad51 recruitment to DNA double-strand lesion for repair and may ultimately cause tumor cell death. In conclusion, this study provides a concrete experience and an alternate strategy of ATO/AZD therapy for patients with R/M HNSCC.