Objective To explore the related factors affecting weaning outcome in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and respiratory failure undergoing invasive mechanical ventilation. Methods The clinical data of 80 patients with AECOPD and respiratory failure who received invasive mechanical ventilation from October 2023 to February 2025 were retrospectively analyzed. Based on the weaning outcome, the patients were divided into weaning success group and weaning failure group. The differences in basic data, mechanical ventilation time, acute physiology and chronic health evaluation II (APACHE II) score and biochemical indexes were compared, and the independent factors affecting the weaning outcome were analyzed. Results This study ultimately included 80 patients with AECOPD and respiratory failure, including 66 cases (2.5%) with successful weaning and 14 cases (17.5%) with failed weaning. The proportion of patients with age≥60 years old, the number of diabetic patients, the number of smokers, mechanical ventilation time, APACHE II score and C-reactive protein (CRP) before weaning in failure group were higher compared to success group (all P＜0.05). Failure group showed lower serum albumin (ALB) and hemoglobin (Hb) than success group (both P＜0.05). Logistic regression analysis revealed that history of diabetes mellitus, long ventilation time, low ALB level before weaning and low Hb level before weaning were all the independent factors affecting weaning outcome (all P＜0.05). Conclusion The weaning failure rate of invasive mechanical ventilation is high in patients with AECOPD and respiratory failure. Diabetes mellitus, prolonged mechanical ventilation time, and hypoalbuminemia and anemia before weaning are independent risk factors for weaning failure in patients with AECOPD and respiratory failure. Clinically, it is necessary to formulate effective measures according to the conditions and risk factors of patients to improve the weaning outcome of patients.