Objective To evaluate the efficacy and prognosis of neonatal severe meconium aspiration syndrome (MAS) ventilator combined with pulmonary surfactant (PS). Methods According to the random number table method, 112 cases of neonatal severe MAS children admitted to our hospital from May 2015 to June 2017 were divided into control group (56 cases) and study group (56 cases). The patients in the control group were treated with ventilator mechanical ventilation, and the patients in the study group were treated with PS on the basis of treatment in the control group. The ventilator parameters, blood gas analysis, inflammatory factors, comorbidities and outcome were compared and analyzed in both groups. Results The mean airway pressure (MAP), inhalation oxygen volume fraction (FiO2), peak pressure (PIP) and on the machine were lower than those in the control group. The levels of PCO2 and IL-10 in the combined group were higher than those in the control group at 2h, 12h and 24h after treatment, and the levels of oxygen partial pressure (PO2) and IL-8 were lower than those in the control group. There was no significant difference between the two groups in hypoxic - ischemic encephalopathy and intraventricular hemorrhage and mortality. The incidence of ventilator-associated pneumonia (VAP) and pulmonary air leakage in the combined group were lower than those in the control group. Conclusion Neonatal severe MAS with ventilator combined with PS treatment will help shorten the treatment time, improve blood gas analysis, reduce the inflammatory response, reduce the risk of complications and death.