Objective To compare the effects of different nebulization gases on the dynamic changes in partial pressure of carbon dioxide (PaCO2) and treatment outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) receiving non-invasive ventilation. Methods Sixty-four patients with AECOPD were randomly divided into the oxygen group and the air group, with 32 patients in each group. The oxygen group received oxygen-driven nebulization therapy during non-invasive ventilation, while the air group received air-driven nebulization therapy. The patients′ transcutaneous partial pressure of carbon dioxide (PtCO2) was recorded at 0, 5, 10, 15 min of nebulization, and 5, 10, 15 min after nebulization. Arterial blood gas analysis, COPD assessment test (CAT) score, and sputum symptom score were recorded before treatment, on the 4th day of treatment, and on the 7th day of treatment.Results Thirty cases in each group completed the study .There were statistical differences in the comparison group effect of repeated measurements of PtCO2 between the two groups (all P<0.05). After treatment, PaCO2, pH value, CAT score, and sputum symptom score improved in both groups, and the difference in PaCO2 between the two groups on the 7th day of treatment was statistically significant (P<0.05). Conclusion Both oxygen and air nebulization can achieve good therapeutic effects. The oxygen group can maintain a relatively stable PtCO2 during nebulization, while the air group can reduce PtCO2 during nebulization, which is suitable for type II respiratory failure patients with AECOPD.