Objective To investigate the efficacy and safety of local intra-arterial chemotherapy combined with immune checkpoint inhibitors in the treatment of unresectable head and neck squamous cell carcinoma (HNSCC). Methods A retrospective analysis was conducted on the clinical data of eight patients diagnosed with unresectable HNSCC at our hospital from January to December 2023. All patients were diagnosed by pathological diagnosis and treated with intra-arterial chemotherapy combined with immune checkpoint inhibitors. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse reactions were observed. Results The study cohort consisted of seven men and one woman, with a median age of 58.4 +/- 13.1 years. Five patients were at stage IVA, one at stage IVB, and two at stage IVC. One patient was lost to follow-up, and among the 7 patients with complete data, the ORR was 85.7%. The median PFS and OS in the overall population were not achieved, and the patient tolerated the treatment well with no significant adverse effects. Conclusion Local intra-arterial chemotherapy combined with immune checkpoint inhibitors is an important future exploration direction for the treatment of unresectable HNSCC.