Background: Patients with platinum-refractory disease who experience early treatment failure of head and neck squamous cell carcinoma (HNSCC) exhibit a dismal prognosis. Metronomic chemotherapy is a promising treatment schedule in clinical practice for HNSCC. Oral metronomic chemotherapy with methotrexate, celecoxib, and capecitabine regimens was effective because of overcoming drug resistance and antiangiogenesis effects. Aimed: To improve treatment outcomes of recurrent, platinum–resistant, and metastatic HNSCC. Method: In this prospective clinical trial, 94 patients diagnosed with advanced/recurrent HNSCC were enrolled. Patients received triple therapy, including capecitabine, methotrexate, and celecoxib. The multidisciplinary team evaluated treatment toxicity, response, progression-free survival (PFS), and overall survival (OS). Kaplan Meier curve was used to show the survival/Wilcoxon signed-rank test. Results: The most common observable toxicity findings were grade 1 plus grade 2 fatigue in 49 (52.1%), oral mucositis in 40 patients (42.5%), and anemia in 37 patients (39.4%) in the absence of notified grade 3 or 4 toxicities. 20 patients out of 94 exhibited complete responses (CRs). One and two-year PFS rates were 16% and 11.7%; and one and two-year OS were 21.3% and 17 %, respectively. Two median years PFS was 4 months, and two median years OS was 8 months (SPSS 16.0 for Windows, Wilcoxon signed-rank test, P value ≤ 0.05 is significant). Conclusion: Capecitabine, methotrexate, and celecoxib combined chemotherapy are effective and tolerable in treating platinum-refractory, recurrent, and metastatic HNSCC with non-inferior clinical outcome results, especially in poor societies