Background: Bronchiectasis-chronic obstructive pulmonary disease (COPD) overlap (BCO) is a neglected area of trials, and it is not covered by guidelines for clinical practice. Methods: Using the National Health Insurance Research Database of Taiwan, COPD patients with or without bronchiectasis from 2000 to 2009 were enrolled as the BCO and COPD alone cohorts, respectively. Patients followed for <28 days, diagnosed with COPD who were not prescribed with COPD medications, and those diagnosed with bronchiectasis who did not receive a chest X-ray or computed tomography were excluded. The primary endpoints were acute exacerbations and mortality. Results: There were 831 patients in the BCO cohort and 3321 patients in the COPD alone cohort, covering 3763.08 and 17,348.95 person-years, respectively, from 2000 to 2011. The BCO cohort had higher risk for exacerbations (adjusted hazard ratio (HR) 2.26, 95% confidence interval (CI) 1.94–2.63) and mortality (HR 1.46, 95% CI 1.24–1.73) than the COPD alone cohort. In the patients overall, the use of statins, macrolides, and mucolytic agents was associated with significantly lower risks of acute exacerbations (statins, HR 0.37, 95% CI 0.29–0.46; macrolides, HR 0.65, 95% CI 0.45–0.93; mucolytic agents, HR 0.68, 95% CI 0.59–0.78). Statins were associated with a significantly lower risk of mortality (HR 0.32, 95% CI 0.25–0.41). In the BCO group, statins and mucolytic agents use was associated with significantly lower risks of acute exacerbations (statins, HR 0.44, 95% CI 0.29–0.65; mucolytic agents, HR 0.58, 95% CI 0.45–0.75). Conclusion: Statins and mucolytic agents use may lower risk of acute exacerbation in patients with BCO.