Hypoxemia is a common complication in the pediatric operating room during endotracheal intubation and airway procedures and is a precursor to serious adverse events. Small children and infants are at greater risk of hypoxemia due to their high metabolic requirements and propensity to alveolar collapse during general anesthesia. To improve the care and safety of this vulnerable population, continued efforts must be directed to mitigate hypoxemia and the risk of subsequent serious adverse events. Apneic oxygenation has been shown to significantly prolong the safe apnea time until desaturation in infants, children, and adults and may reduce the incidence of desaturation during emergency intubation of critically ill patients. Successful apneic oxygenation depends on adequate preoxygenation, patent upper and lower airways, and a source of continuous oxygen delivery. Humidified, high-flow nasal oxygenation systems have been shown to provide excellent conditions for effective apneic oxygenation in adults and children and have the added benefit of providing some carbon dioxide clearance in adults; although, this latter benefit has not been shown in children. Humidified, high-flow nasal oxygenation systems may also be useful during spontaneous ventilation for airway procedures in children by minimizing room air entrainment and maintaining adequate oxygenation allowing for a deeper anesthetic. The use of apneic oxygenation and humidified, high-flow nasal oxygenation systems in the pediatric operating room reduces the incidence of hypoxemia and may be effective in decreasing related complications.