OBJECTIVES: The option is rare for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) failed to prior-line immune checkpoint inhibitors (ICIs) and cetuximab-based treatment. The efficacy of salvage therapy was unsatisfied. MATERIALS AND METHODS: We collected the clinical data of R/M HNSCC patients progressed from prior-line immunotherapy and cetuximab therapy, and retrospectively analyzed the efficacy and toxicity of anlotinib-based therapy in these patients. RESULTS: In total, 24 eligible participants were accrued between October 2021 and November 2024. Up to the cutoff time of November 1st, 2024, the objective response rate was 37.5%. Survival analysis revealed the median progression-free survival and overall survival was 4.27 months (95% CI, 1.53-7.01 months) and 8.67 months (95% CI, 5.62-11.72 months), respectively. For the safety, most common TRAEs with any grades were hypertension, hand-foot syndrome, gastrointestinal response, hemorrhage, hepatic dysfunction, and fatigue. Grade 3 or more TRAEs were observed in 3 (12.5%) patients, and no Grade 5 TRAEs were occurred. CONCLUSIONS: Our observations indicated that anlotinib-based therapy had considerable efficacy and well tolerance in R/M HNSCC patients failed to ICIs and cetuximab-based therapy, and might be acted as a novel and potentially effective option in later-line treatment of R/M HNSCC.