Abstract: Objective To evaluate the clinical efficacy of high-flow nasal cannula (HFNC) in the treatment of neonatal pneumonia with respiratory failure. Methods A total of 54 neonates with severe pneumonia and respiratory failure were randomly divided into two groups using the random number table method, with 27 cases in each group. The observation group was given HFNC, while the control group was given normal bubble oxygen humidification device to inhale oxygen. The heart rate, respiratory rate, partial pressure of oxygen in arterial blood (PaO₂), partial pressure of carbon dioxide in arterial blood (PaCO₂) and pulse oxygen saturation (SpO₂) of the two groups were observed before and 1, 12 and 24 h after treatment, respectively. The differences of sputum viscosity, tracheal intubation mechanical ventilation rate, continuous positive pressure ventilation (CPAP) treatment rate and length of stay in neonatal intensive care unit (NICU) between the two groups were compared. Results Compared with the control group, the heart rate, respiratory rate, PaO₂, PaCO₂ and SpO₂ of the observation group were significantly improved (P<0.05). The length of stay in NICU in the observation group was significantly shorter than that in the control group (P<0.05). The sputum viscosity of the observation group was lower than that of the control group (P<0.05). Conclusions HFNC can effectively treat neonate with severe pneumonia complicated with respiratory failure, alleviate clinical symptoms, improve pulmonary oxygenation function, reduce complications and improve prognosis.