Abstract Background Noninvasive ventilation (NIV) is the recommended mode of ventilation used in acute respiratory failure secondary to an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Recent data has shown that high-flow nasal cannula (HFNC) treatment can be an alternative for patients with hypercapnic respiratory failure. The purpose of this study is to evaluate HFNC with sequential NIV versus NIV alone as the initial ventilatory strategy in AECOPD. Methods This investigator-initiated, unblinded, single center, randomized controlled trial will be conducted in the emergency department, emergency intensive care unit, or respiratory intensive care unit of a tertiary-care urban teaching hospital. A total of 66 patients will be enrolled and randomized into the intervention group (HFNC with sequential NIV) or the control group (NIV group). The primary endpoint will be the mean difference in PaCO₂ from baseline to 24 h after randomization. Secondary endpoints include the mean difference in PaCO₂ from baseline to 6, 12, and 18 h, as well as the dyspnea score, overall discomfort score, rate of treatment failure, respiratory rate, rate of endotracheal intubation, length of hospital stay, and mortality. Discussion Taking the advantages of both HFNC and NIV on AECOPD patients into account, we designed this clinical trial to investigate the combination of these ventilatory strategies. This trial will help us understand how HFNC with sequential NIV compares to NIV alone in treating AECOPD patients. Trial registration ChiCTR2100054809.