IntroductionNoninvasive ventilation (NIV) is widely used for sequential extubation in patients with chronic obstructive pulmonary disease (COPD). However, NIV may cause many adverse events such as claustrophobia, facial skin compression, air leakage, bloating, and even reflux aspiration, resulting in poor patient compliance/tolerance and high failure rate, especially for older adults who are at high risk of communication difficulties and consciousness disorder. High-flow nasal cannula (HFNC) oxygen therapy is a new alternative support to NIV, but whether it can effectively reduce the rate of re-intubation after extubation in elderly patients with COPD remains controversial. The purpose of this study is to explore the safety and efficacy of HFNC versus NIV for elderly COPD patients after extubation.Methods and analysisThis study is an investigator-initiated, single-center, prospective, non-inferior, randomized controlled trial. Elderly patients (age > 65 years) who have received invasive ventilation and was diagnosed with COPD will be randomly assigned to HFNC group or NIV group immediately after extubation with a planned enrollment of 168 patients. The primary outcomes will be reintubation rates at 72 h and 7 days after extubation. Secondary outcomes will include treatment failure, post-extubation vital signs and arterial blood gases, the scores of compliance and comfort of patients, duration of respiratory support after extubation, respiratory support related adverse events, sleep quality scores, usage of sedative and analgesic drugs after extubation, and the incidence of delirium. Additionally, clinical outcomes such as ventilator-free days at 28 days post-randomization, tracheotomy rate, duration of intensive care unit (ICU) and hospital stay, ICU and hospital mortality will be evaluated.Ethics and disseminationThis study has been approved by the Ethics Committee of West China Hospital of Sichuan University (2023–2284). Informed consent is required. It is expected that a follow-up randomized controlled trial will be conducted. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences.Trial registrationThe study was retrospectively registered at ClinicalTrials.gov (ChiCTR2400087312).