Abstract: Objective To explore a new approach for treating neonatal acute respiratory distress syndrome (NARDS) by comparing the clinical efficacy and adverse reactions of intratracheal instillation of pulmonary surfactant (PS) alone or in combination with budesonide in NARDS of different etiologies. Methods A controlled study was conducted on children with NARDS who were admitted to Xuzhou Central Hospital from October 2022 to November 2024 and met the Montreux criteria. They were randomly divided into two groups: a PS group (intratracheal instillation of PS) and a PSB group (intratracheal instillation of PS + budesonide). Each group was further divided into subgroups based on direct or indirect etiological factors. Parameters including fraction of inspired oxygen (FiO₂), oxygenation index (OI), duration of respiratory support, repeated PS use, and steroid-related adverse complications were compared. Results A total of 42 cases were included in the PS group and 44 cases in the PSB group. The OI at 12 h and 24 h after administration was lower in the PSB group than in the PS group (P<0.05). No significant differences were observed between the two groups in terms of FiO₂, repeat PS use rate, duration of respiratory support, or short-term efficacy and steroid-related adverse outcomes (P>0.05). Within the PS group, the FiO₂ at 12 h and 24 h after administration and the repeat PS use rate in the indirect lung injury subgroup were higher than those in the direct lung injury subgroup, while the duration of respiratory support and length of hospitalization stay were shorter than in the direct lung injury subgroup (P<0.05).Within the PSB group, the OI and FiO₂ at 12 h and 24 h after administration and the repeat PS use rate in the indirect lung injury subgroup were higher than those in the direct lung injury subgroup, while the duration of respiratory support and length of hospitalization stay were shorter than in the direct lung injury subgroup (P<0.05). In the direct lung injury subgroup, the OI at 12 h and 24 h after administration, FiO₂ at 24 h after administration, and the length of hospitalization stay in the PSB group were all significantly lower than those in the PS group (P<0.05). No significant differences were observed in clinical efficacy or adverse outcomes between the indirect lung injury subgroups of the two groups (P>0.05). Conclusions With PS alone, intratracheal instillation of PS combined with budesonide for NARDS can more effectively attenuate lung injury, which may mainly reduce the lung injury caused by direct lung injury factors in NARDS, and accelerate its recovery, without increasing the risk of glucocorticoid-related complications and short-term adverse outcomes.