Objective: The current study aimed to analyze the short-term and long-term curative effects of nitric oxide (NO) inhalation combined with high-frequency oscillatory ventilation (HFOV) on neonatal severe hypoxemia. Materials and Methods: A total of 98 neonates meeting the inclusion criteria were retrospectively analyzed. The control group comprised of 48 neonates and the NO inhalation group consisted of 50 neonates. In the control group, conventional mechanical ventilation was replaced by HFOV. In the experimental group, NO inhalation combined with HFOV was performed. The death rates within 28 days, mechanical ventilation and oxygen therapy time, and complications in both groups were observed. The survivors in both groups were followed up for 18 months for neural development evaluation. Results: The treatment group showed a significantly lower death rate and noticeably shorter mechanical ventilation and oxygen therapy time than the control group (8% vs. 22.9% with t = 4.20 and p < 0.05; 5.84 ± 3.36 days vs. 8.05 ± 5.48 days with t = 2.42 and p < 0.05; and 8.02 ± 4.31 days vs. 12.45 ± 5.14 days with t = 4.63 and p < 0.001). They did not show significant differences with regards to the complications and the incidences of cerebral palsy, hearing and visual impairments, and severe nervous damage (p > 0.05). Conclusion: NO inhalation combined with HFOV significantly decreases the death rate of neonates with severe hypoxemia and reduces their mechanical ventilation and oxygen therapy time. It does not increase early adverse effects or affect long-term neurodevelopment.