Objective To explore the clinical value of non-invasive high-frequency oscillatory ventilation (NHFOV) combined with budesonide nebulization in managing neonatal respiratory distress syndrome (NRDS) after extubation and ventilator weaning.Method A retrospective analysis was conducted on 76 newborns with NRDS admitted to the Neonatal Department of Northwest Women and Children's Hospital from June 2020 to October 2022. All of them were given non-invasive ventilation after extubation and weaning from the ventilator. According to the non-invasive ventilation mode, they were divided into the observation group and the control group. In the control group, 36 cases received nasal continuous positive airway pressure (NCPAP) ventilation. In the observation group, 40 cases received NHFOV. Additionally, both groups were treated with budesonide nebulization. The two groups were compared in terms of arterial blood gas parameters [partial pressure of oxygen (PaO₂) and partial pressure of carbon dioxide (PaCO₂)], Newborn Early Warning Score (NEWS), pulmonary surfactant protein D (SP-D), aquaporin-5 (AQP-5) in lung tissues, respiratory dynamics (airway resistance and lung compliance), pulmonary function [forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) ], and incidence of complications.Results The effective rate of the observation group was higher than that of the control group (P < 0.05). The increase in PaO? before and after treatment in the observation group was lower than that in the control group (P < 0.05), and the decreases in PaCO₂ and NEWS scores before and after treatment in the observation group were both lower than those in the control group (P < 0.05). The increases of SP-D and AQP-5 levels before and after treatment in the observation group were both greater than those in the control group (P < 0.05). The decrease in airway resistance before and after treatment in the observation group was lower than that in the control group (P < 0.05), and the increase in lung compliance before and after treatment in the observation group was also lower than that in the control group (P < 0.05). The differences in FEV₁ and FVC before and after treatment in the observation group were both lower than those in the control group (P < 0.05). The comparison of the incidence of complications between the control group and the observation group showed no statistically significant difference (P > 0.05).Conclusion The use of NHFOV combined with budesonide nebulization after extubation and ventilator weaning in infants with NRDS can improve respiratory function and oxygenation, and enhance lung compliance.