Objective: To address the effectiveness and safety of early airway utilization of budesonide and surfactant for BPD prevention in premature infants with RDS. Methods: PubMed, Web of Science, EMBASE, Cochrane Library, Wanfang, CQ VIP and China National Knowledge Infrastructure databases were searched from the inception to May 2021. Stata 16.0 software was used for statistical analysis. Results: This meta-analysis suggested that early combined utilization of budesonide and surfactant by airway tended to have a superiority on BPD incidence (RR=0.63;95%CI:0.54～0.73, P<0.001), mortality (RR=0.63;95%CI:0.43～0.94, P=0.022) and the composite outcome of BPD or mortality (RR=0.59;95%CI:0.49～0.70, P<0.001), the reuse incidence of surfactant (RR=0.54; 95%CI:0.45～0.65, P<0.001), the duration of assisted ventilation (SMD=-1.14;95%CI: -1.58 ～ -0.70, P<0.001), invasive ventilation (SMD=-1.33;95%CI: -1.76～-0.90, P<0.001), and hospital stays (SMD=-1.20;95%CI: -1.88～-0.51, P=0.001) in preterm infants with RDS. And these benefits were not associated with increased adverse outcomes. Furthermore, a decreased incidence of PDA (RR=0.80; 95%CI:0.64～0.99, P=0.041) was found in test group. Subgroup analysis based on budesonide delivery methods (inhalation or intratracheal instillation) indicated that the decrease of mortality (RR=0.62;95%CI:0.41～0.95, P=0.026), duration of assisted ventilation (SMD=-0.95;95%CI: -1.30～-0.61, P<0.001) and hospital stays (SMD=-1.38;95%CI: -2.33～-0.43, P=0.004) were mainly in budesonide intratracheal instillation subgroup. Conclusions: This meta-analysis suggested that early combined utilization of budesonide and surfactant by airway might be an effective and safe clinical practice for BPD prevention in premature infants with RDS, especially when budesonide was delivered by intratracheal instillation.