Background The safety and efficacy of transbronchial microwave ablation (TMA) therapy in patients with malignant central airway obstruction (CAO) with respiratory failure remains unclear. Methods A total of 38 patients with advanced non-small cell lung cancer (NSCLC) or lung metastases with malignant endoluminal obstruction received TMA therapy under moderate sedation and high fractions of inspired oxygen (FiO 2 ). The success rate of airway patency restoration, complication rate, and overall survival time (OS) from the initiation of TMA therapy were compared in the following two groups of patients with malignant CAO patients: the group with respiratory failure (PaO 2 /FiO 2  ≤ 300) (RF group, n  = 10) and the group without respiratory failure (PaO 2 /FiO 2  > 300) (non-RF group, n  = 28) at the time of the TMA therapy. Results Both the RF group and non-RF group received a median of two sessions of TMA. There was no significant difference in the percentage of patients who showed restored airway patency after the first session of TMA (90% vs. 96%), in the complication rate of TMA therapy (10% vs. 11%), or in the OS (7.1 months vs. 9.1 months) between the RF group and the non-RF group. Multivariate analysis identified no significant association between TMA therapy and the risk of death in malignant CAO patients with respiratory failure ( p  = 0.196). Conclusion TMA therapy under moderate sedation was well tolerated and effective in patients with malignant CAO, including those with respiratory failure.