To determine the safety and effectiveness of current pharmacotherapies consisting of long-acting beta-agonist (LABA) and/or inhaled corticosteroids (ICS) in patients with asthma-COPD overlap. A systematic search was conducted using the PubMed, EMBASE, and Web of Science databases up to June 2018. Only studies comparing the safety and effectiveness of LABA and/or ICS in patients with asthma-COPD overlap were included. A meta-analysis was performed to calculate risk ratio (RR) and 95% confidence interval (CI) using Inverse Variance Random-effects model. From a total of 3382 articles retrieved, three randomized controlled trials (RCTs), six cohort studies (CS), one nested case control study fulfilled the inclusion criteria for three independent meta-analyses representing 181,603 participants. Three CS results show LABA was associated with decreased risk of myocardial infarction (combined RR: 0.80, 95% CI 0.74-0.87) versus non-LABA use; ICS/LABA was associated with a lower risk of death or hospitalization (combined RR: 0.82, 95% CI 0.75-0.90) compared to no use. Results from RCTs, no clear difference in lung function decline in FEV was found (combined mean difference: 0.08, 95% CI 0.15-0.32) in patients receiving ICS and/or LABA compared to placebo. However, due to lack of data, exacerbations, fractures and nontuberculous mycobacterial pulmonary disease outcomes were not meta-analyzed. Among patients with asthma-COPD overlap, LABA is associated with decreased risk of myocardial infarction; and the combination therapy of ICS/LABA appears to reduce the risk of death or hospitalization. More studies of quality data and larger number of patients are needed. PROSPERO (CRD42018090863).