Objective This study aimed to assess whether the short-term use of macrolide antibiotics during hospitalization can reduce in-hospital all-cause mortality compared to non-macrolide treatment in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods A propensity score (PS) matching analysis was performed using retrospective data from the admission records of AECOPD patients in the medical general ward and medical intensive care unit of a tertiary care center between October 2015 and September 2018. The multivariable Cox proportional hazard model was performed to eliminate residual confounding after the PS analysis. Results The mortality rate was 11.1% of 1528 admissions in the PS matching cohort. Approximately 70% of patients had respiratory failure requiring intubation on initial admission, and 34% had pneumonia. Macrolide treatment significantly reduced in-hospital mortality among AECOPD patients (adjusted hazard ratio, 0.55; 95% confidence interval 0.32–0.96; P =0.034). Clarithromycin was the most commonly prescribed macrolide (80%). Conclusion Macrolide antibiotics reduced in-hospital mortality in hospitalized AECOPD patients. The combination of antimicrobial and immunomodulatory effects of macrolide treatment could play an essential role.