Background: Near-infrared spectroscopy (NIRS) provides the capability of monitoring oxygenation levels in cerebral microscopic vessels, enabling the operator to observe the spontaneous changes in the levels of hemoglobin concentration in tissue and interpret the resulting fluctuations. The current study tried to investigate whether brain's autoregulatory mechanisms in premature newborns have the potential to prevent the adverse effects caused by asynchronous changes of pressure in the rib cage. Therefore, NIRS method was applied to newborns that were alternatively shifted from nasal continuous positive airway pressure (nCPAP) to nasal intermittent positive pressure ventilation (NIPPV) and vice versa. Methods: This study was done as a crossover randomized clinical trial on 30 very low-weight newborns under nCPAP, who had received surfactant as a result of respiratory distress syndrome diagnosis, from April 2015 to April 2016, in Isfahan Shahid Beheshti Educational Hospital. The newborns were 72 h old, experiencing continuous distending pressure (CDP) = 4–6 cmH2O with FiO2 = 30%–40%. The respiratory support would alternate from nCPAP to NIPPV and vice versa (with indicators of expiratory PAP (EPAP) = CDP and inspiratory PAP = EPAP + 4 cmH2O), and the cerebral regional oxygen saturation (CrSO2) was monitored using NIRS. Results: The study results indicated that newborns significantly showed higher levels of CrSO2(84.93,P= 0.005) and oxygenation (94.63,P= 0.007) under nCPAP rather than NIPPV (82.43 and 93.43, respectively). The respiratory rate was also meaningfully slower when newborns were under nCPAP (P = 0.013). Conclusions: This study revealed that applying NIPPV may have an unfavorable effect on the premature newborn's brain tissue perfusion. However, more studies are needed to ensure solid outcomes.