Objective To explore the role of pulmonary surfactant (PS) combined with budesonide in improving oxygenation and clinical outcomes of neonatal acute respiratory distress syndrome (ARDS). Methods The present study is a historically controlled trial. Infants with ARDS requiring mechanical ventilation and PS replacement therapy were collected from the neonatal unit of Southwest Medical University. Those from January 2022 to November 2022 were set as intervention group (PS+budesonid, n=35), treated with intratracheal instillation of a mixed suspension of budesonide (0.25 mg/kg) and PS (200 mg/kg), and continuous budesonide nebulization (0.25 mg/kg, twice per day) until withdrawal, then compared with a historical cohort, who just received intratracheal instillation of PS (200 mg/kg) (January 2020-December 2021, PS group, n=35). Baseline data such as gender, mode of delivery, 1 min and 5 min Apgar score, birth weight, gestational age, time of onset, and cause of onset were recorded in both groups. The oxygenation and clinical outcomes of infants were compared between the two groups, including: (1) Arterial blood gas analysis indicators, such as partial pressure of oxygen (PaO₂) and oxygenation index (OI) before treatment and at 6, 12 and 24 hours of treatment; (2) Clinical observation and evaluation indicators, such as the time to withdrawal, duration of oxygen supplementation, length of stay, improvement of the radiological images of the lungs at 72 h of treatment, and repeated PS use; (3) Blood chemistry indicators, such as white blood cell (WBC), neutrocyte (NEU), procalcitonin (PCT) before treatment and at 3 and 7 days of treatment; and (4) Observation indicators of complications, weight growth, and mortality outcomes, such as the incidences of intracranial hemorrhage, gastrointestinal hemorrhage, neonatal necrotizing enterocolitis (NEC), and hyperglycemia, weight growth, and fatality rate. Results The differences in baseline data between the two groups were not statistically different (P>0.05). The levels of PaO₂ of the two groups were increased after treatment for different time periods, while the levels of OI were decreased (P<0.001), and the levels of above indexes changed more significantly in PS+budesonide group than those in PS group (P<0.05). The time to withdrawal, duration of oxygen supplementation, and length of stay in PS+budesonide group were shorter than those in PS group; the radiological images of the lungs showed that the pulmonary inflammation absorption was significantly better in PS+budesonide group than that in PS group, while no significant difference between the two groups of infants with repeated PS use. The NEU was significantly higher in PS+budesonide group than in PS group at 3 d and 7 d of treatment (P<0.001); and at 3 days of treatment, the PCT levels were significantly lower in PS+budesonide group than that in PS group (P<0.05). The incidences of intracranial hemorrhage, gastrointestinal hemorrhage, NEC, hyperglycemia, weight growth, and fatality rate were not significantly different between the two groups (P>0.05). Conclusion The use of budesonide in addition to surfactant may improve the oxygenation of neonates with ARDS, improve the inflammatory infiltrates in lungs, shorten the duration of mechanical ventilation and oxygen supplementation, and without short-term complications associated with budesonide use.