Objective To compare the efficacy of nasal bi-level positive airway pressure (BiPAP) with nasal continuous positive airway pressure (NCPAP) therapy in very low birth weight infants with respiratory distress syndrome (RDS). Methods A total of 95 cases of very low birth weight infants with RDS admitted to Department of Neonatology, Kaifeng Maternity and Child Health Care Hospital from January 2021 to December 2023 were included in the study. The children were divided into the NCPAP group (n=48 cases) and the BiPAP group (n=47 cases) according to the mode of transnasal positive airway pressure. Clinical indexes were compared between groups, blood gas indexes [partial pressure of oxygen in arterial blood (PaO2), partial pressure of carbon dioxide in arterial blood (PaCO2), oxygenation index (OI)], serum inflammatory indexes [procalcitonin (PCT), tumor necrosis factor-α (TNF-α)] before treatment, and at 12h and 24h after treatment. The incidence of complications was also recorded, including nasal injury, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), periventricular leukomalacia (PVL), intraventricular hemorrhage (IVH), and air leakage. Results There was no significant difference in the endotracheal intubation rate between the two groups after 28 days (P>0.05). The total oxygen consumption time and hospitalization time in the NCPAP group were longer than those in the BiPAP group (all P <0.05). Compared with before treatment, the levels of PaO2 and OI were significantly increased, while PaCO2 was significantly decreased in both groups at 12h and 24h after treatment (all P <0.05). At 12h and 24h after treatment, the PaO2 and OI values in the BiPAP group were observed to be superior to those in the NCPAP group, while the PaCO2 levels were noted to be lower (all P<0.05). Additionally, the incidence of complications within the BiPAP group was determined to be significantly less than that of the NCPAP group (P<0.05). Conclusion Compared to NCPAP, the application of nasal BiPAP is more efficacious in the treatment of very low birth weight infants with RDS, thereby facilitating enhanced blood gas parameters, diminishing inflammatory responses, and lowering the incidence of complications.