Background: A large percentage of premature newborns are affected by respiratory distress syndrome (RDS), which has a substantial negative influence on morbidity and death. A significant association exists between neonatal positioning and clinical outcomes in infants with respiratory distress syndrome. This study aims to evaluate the effect of different neonatal positioning strategies on the respiratory status improvement in neonates diagnosed with respiratory distress syndrome. Methods: In this clinical trial interventional versus control study, 60 newborns with respiratory distress syndrome receiving oxygen therapy were treated in the neonatal intensive care units (NICU) of medical insurance hospitals in Egypt, Ministry of Health hospitals in Kuwait, and Zagazig University Hospital. Their mean age was 1–14 days with male-to-female ratio ≈ 3:1, divided into 2 groups (30 neonates put in supine position and 30 neonates put in prone position), The duration of N-CPAP, the number of prescribed doses of surfactant, the need for mechanical ventilation, time to full feed, and positive end-expiratory pressure (PEEP) were investigated in this study. Results: In prone postures, the results demonstrated improved oxygenation levels, as measured by arterial blood gases and oxygen saturation following prone position, and a statistically significant decrease in heart rate at the second hour. There was statistically significant decrease in CO2 in prone positions in 2nd hour after prone position, NICU duration, duration of oxygen, MV usage and mortality. Conclusion : the prone position significantly improves oxygenation in neonates with respiratory distress syndrome and may be a beneficial adjunctive therapy in the NICU.