Objective: Despite the routine use of antenatal steroids, exogenous surfactants, and different noninvasive ventilation methods, many extremely low gestational age neonates, preterm, and term infants eventually require invasive ventilation. In addition to prematurity, mechanical ventilation itself can induce ventilator-induced lung injury leading to lifelong pulmonary sequelae. Besides conventional mechanical ventilation, high-frequency oscillatory ventilation (HFOV) with tidal volumes below dead space and high ventilation frequencies is used either as a primary or rescue therapy in severe neonatal respiratory failure. Methods and Results: Applying a high-resolution computational lung modeling technique in a preterm infant, we studied three different high-frequency ventilation settings as well as conventional ventilation (CV) settings. Evaluating the computed oxygen delivery (OD) and lung mechanics (LM) we outline for the first time how changing ventilator settings from CV to HFOV lead to significant improvements in OD and LM. Conclusion: This personalized “digital twin” strategy advances our general knowledge of protective ventilation strategies in neonatal care and can support decisions on various modes of ventilatory therapy at high frequencies.