<b><i>Background:</i></b> Although antibiotic treatment is recommended for acute exacerbations of chronic obstructive pulmonary disease (AECOPD), its value in real-world settings is still controversial. <b><i>Objectives:</i></b> This study aimed to evaluate the short- and long-term effects of antibiotic treatment on AECOPD outpatients. <b><i>Methods:</i></b> A cohort study was conducted under the PharmLines Initiative. We included participants with a first recorded diagnosis of COPD who received systemic glucocorticoid treatment for an AECOPD episode. The exposed and reference groups were defined based on any antibiotic prescription during the AECOPD treatment. The short-term outcome was AECOPD treatment failure within 14–30 days after the index date. The long-term outcome was time to the next exacerbation. Adjustment for confounding was made using propensity scores. <b><i>Results:</i></b> Of the 1,105 AECOPD patients, antibiotics were prescribed to 518 patients (46.9%) while 587 patients (53.1%) received no antibiotics. The overall antibiotic use was associated with a relative risk reduction of AECOPD treatment failure by 37% compared with the reference group (adjusted odds ratio [aOR] 0.63 [95% CI: 0.40–0.99]). Protective effects were similar for doxycycline, macrolides, and co-amoxiclav, although only the effect of doxycycline was statistically significant (aOR 0.53 [95% CI: 0.28–0.99]). No protective effect was seen for amoxicillin (aOR 1.49 [95% CI: 0.78–2.84]). The risk of and time to the next exacerbation was similar for both groups. <b><i>Conclusion:</i></b> Overall, antibiotic treatment, notably with doxycycline, supplementing systemic glucocorticoids reduces short-term AECOPD treatment failure in real-world outpatient settings. No long-term beneficial effects of antibiotic treatment on AECOPD were found for the prevention of subsequent exacerbations.