Objective To investigate the clinical effect of combination therapy with high-frequency oscillation ventilation (HFOV), pulmonary surfactant (PS) and inhaled nitric oxide (iNO) in the treatment of neonatal hypoxemic respiratory failure (HRF). Methods A total of 116 neonates with HRF were studied, and they were randomly divided into two groups: triple therapy (n=58) and dual therapy (n=58). The triple therapy group received HFOV, PS, and iNO, while the dual therapy group received HFOV and iNO. Blood gas values, PaO₂/FiO₂ (P/F), oxygenation index (OI), and pulmonary arterial pressure (PA) were determined before treatment and after 24 and 48 hours of treatment. Among the neonates with different P/F ratios and OI values and with or without persistent pulmonary hypertension of the newborn (PPHN), the treatment outcomes of two groups were compared. Results The durations of mechanical ventilation and iNO therapy in the triple therapy group were significantly shorter than in the dual therapy group (P<0.01). After 24 and 48 hours of treatment, the triple therapy group had significantly improved PaO₂ and PaCO₂ compared with the dual therapy group (P<0.01). After 24 and 48 hours of treatment, the neonates with PPHN in the triple therapy group had significantly decreased PA compared with the dual therapy group (P<0.01). In the cases with a P/F ratio of ≤50, the triple group had a significantly higher cure rate than the dual therapy group (P<0.05). In both groups, the P/F ratios of the neonates who died were significantly lower than those of survivors (P<0.01). In the cases with an OI of ≥40, the triple group had a significantly higher cure rate than the dual therapy group (P<0.05). In both groups, the OI values of the neonates who died were significantly higher than those of survivors (P<0.01). In neonates with PPHN, the triple group had a significantly higher cure rate than the dual therapy group (P<0.05). The triple therapy group had a significantly shorter length of hospital stay (P<0.01) and a significantly higher cure rate (P<0.05) compared with the dual therapy group. There were no significant differences in complications between the two groups (P >0.05). No severe side effect was found during the treatment in either group. Conclusions Triple therapy with HFOV, PS and iNO is a more effective treatment for neonatal HRF compared with the dual therapy with HFOV and iNO. The triple therapy can significantly improve oxygenation and survival rate, providing a new treatment for the neonates with HRF, especially the critical cases who suffer severe lung disease with PPHN and have a P/F ratio of ≤50 or an OI of ≥40.