In physiological conditions, neonatal airways are well-protected against aspiration of fluid or particulate material into the lungs, with laryngeal chemoreflex (LCR) being the most powerful mechanism. Failure of this protection allows substances to enter the lower airways, which starts a series of pathophysiological events initiated by inflammation and surfactant inactivation. The condition is defined as neonatal acute respiratory distress syndrome (ARDS), and its symptoms can range from mild respiratory distress to respiratory failure, often accompanied by persistent pulmonary hypertension (PPHN), in turn even leading to death. The management, therefore, may be very challenging. Areas covered: This review covers protection mechanisms of the neonatal lower airways, the etiology, and pathophysiology of neonatal aspiration syndrome (NAS), its definition in view of current literature, possible treatment options, and future trends. Expert commentary: Inflammation and secondary surfactant deficiency stand in the foreground of neonatal aspiration. Management focuses mainly on appropriate oxygenation, ventilation, improvement in PPHN, and maintenance of systemic circulation, which is largely symptomatic and supportive. Future research is required to evaluate the justification of using exogenous surfactants, antibiotics, anti-inflammatory and antioxidative drugs, or their combinations.