A large proportion of asthmatic patients are treated with protocols resulting from data obtained by randomized controlled trials (RCTs) for which they would not have been eligible. Therefore, the aim of this study was to undertake a quantitative synthesis on real-world evidence comparing single inhaled corticosteroid (ICS)/formoterol maintenance and reliever therapy (SMART) and maintenance ICS/long-acting β₂-adrenoceptor agonist (LABA) + as-needed short-acting β₂-adrenoceptor agonist (SABA). A network meta-analysis of real-world studies was performed to compare SMART with ICS/LABA + as-needed SABA therapies in asthmatic patients. The surface under the cumulative ranking curve analysis was used to rank efficacy. The posterior probability distribution was reported as 95% credible interval (95%CrI). Data of 11,360 asthmatic patients were extracted from 6 studies. SMART including an ICS at medium-dose (MD) was more effective than MD ICS/LABA FDC + as-needed SABA (RR 0.54 95%CrI 0.42–0.69; P < 0.001) and low-dose (LD) SMART (RR 0.82 95%CrI 0.70–0.95; P < 0.05) against severe asthma exacerbation. MD SMART improved the Asthma Control Questionnaire score more than MD ICS/LABA FDC + as-needed SABA (delta effect −0.33 95%CrI −0.62 to −0.01; P < 0.05). The efficacy rank was: MD SMART > LD SMART > ICS + LABA free combination + as-needed SABA > ICS/LABA FDC + as-needed SABA > MD ICS/LABA FDC + as-needed SABA. The findings of this network meta-analysis of real-world evidence, and concordance with the effect estimates resulting from previous meta-analyses of RCTs, suggest that SMART may represent the preferred therapeutic option to reduce the risk of severe exacerbation in adults with moderate to severe asthma.