Objective To investigate the efficacy and safety of noninvasive ventilation (NIV) combined with high-flow nasal cannula oxygen therapy (HFNC) versus NIV as sequential post-extubation therapy in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods This retrospective cohort study enrolled AECOPD patients managed with invasive mechanical ventilation and sequential post-extubation therapy at West China Hospital of Sichuan University from January 2021 to September 2024. The patients were divided into a NIV group and a NIV-HFNC group based on sequential therapy modality. Outcomes included blood gas parameters (at 24h and 48h post-extubation), 7-day delirium incidence post-extubation, 7-day reintubation rate, 28-day mortality, NIV duration, intensive care unit (ICU) length of stay and hospital length of stay. Subgroup analyses were performed for the patients not reintubated within 48h post-extubation. Results A total of 156 patients were included, with 81 patients in the NIV group and 75 patients in the NIV-HFNC group. At 24h and 48h post-extubation, the NIV-HFNC group showed significantly lower PaCO2 (t=3.123, P=0.002; t=4.791, P<0.001) and HCO3– (t=2.313, P=0.022; t=4.605, P<0.001) levels, while pH (t=–2.287, P=0.024) at 48h was significantly higher than that in the NIV group. The 7-day reintubation rate (χ2=14.381, P<0.001) and the NIV duration (z=–3.495, P<0.001) were both significantly lower in the NIV-HFNC group than those in the NIV group. No significant differences were observed in 7-day delirium incidence, 28-day mortality, ICU or hospital length of stay (all P>0.05). Subgroup analyses showed that PaO2 at 48h post-extubation was significantly higher in the NIV-HFNC subgroup compared with the NIV subgroup (t=–2.390, P=0.018) while reintubation rate (χ2=4.693, P=0.030) and NIV duration (z=–4.936, P<0.001) were consistent with the overall results. Conclusion Compared with sequential NIV alone, NIV combined with HFNC as sequential therapy for AECOPD patients demonstrates superiority in improving post-extubation blood gas parameters, reducing reintubation rate and shortening NIV duration, offering a novel post-extubation respiratory support option to improve outcomes.