Background: There are multiple options of treatment in second-line therapy in locally advanced head and neck squamous cell carcinoma (LAHNSCC) with recurrent or metastatic disease. However triple metronomic chemotherapy is oral, affordable, and requires minimal resources. Hence in this study, we compared NCCN-recommended physician choice of standard systemic therapy versus triple metronomic therapy in the second-line treatment of head and neck cancer. Methods: This was a phase 3, multicentric (16 sites), randomized study with a superiority design that was approved by the institutional ethics committees and registered with CTRI (CTRI/2021/08/036002) conducted in India under the aegis of Cancer Research Statistics Foundation. The study recruited LAHNSCC with a recurrent and metastatic disease that either was platinum-refractory or was planned for second-line chemotherapy. The key inclusion criteria were: Age ≥18 years, ECOG PS 0-2, and the presence of normal hematological and biochemical parameters. These patients underwent 1:1 central stratified randomization (Stratification - site of disease & ECOG PS) to either triple metronomic chemotherapy (methotrexate 9 mg/m² PO weekly, celecoxib 200 mg PO twice daily and erlotinib 150 mg PO once daily) or physician choice therapy ( nivolumab or pembrolizumab or cetuximab or taxane or afatinib or 5-FU or capecitabine). The study drugs were administered either till disease progression or the development of intolerable side effects. The primary endpoint of the study is overall survival (OS). The secondary endpoints are adverse events (CTCAE version 5.0), progression-free survival (PFS), and quality of life (EORTC). The sample size required was 114. The OS and PFS were estimated using Kaplan-Meier method and were compared using the log-rank test. Cox proportional hazard model was constructed for the calculation of the hazard ratio. The adverse events were compared using Fisher's test. A p-value of 0.05 was considered significant. Results: At a median follow-up of 258 (95% CI 209-306) days.The median overall survival of the triple metronomic chemotherapy was 181 days (95%CI 142.7-219.2) versus 123 days (95%CI 94-152) in the physician choice therapy arm (P=.0.002). The corresponding hazard ratio of death was 0.58 (95%CI 0.33-0.79, P=0.003). The 6-month OS was 52.9% (95%CI 36.9-65.1) versus 14.8% (95%CI 6.4-26.4). The median progression-free survival was 120 days (95%CI 89.2-150.8) versus 70 days (95% CI 58.2-81.8) in metronomic chemotherapy and in the physician choice therapy arms respectively (P=0.000). The corresponding hazard ratio of progression was 0.5 (95%CI 0.33-0.74, P=0.001). Conclusions: In this phase 3 multicentric study, triple metronomic chemotherapy as second-line therapy had an overall survival and progression-free survival advantage over NCCN-recommended physician choice therapy. Clinical trial information: CTRI/2021/08/036002.