Airway endoscopy procedures, i.e., fiber-optic bronchoscopy executed with both flexible and rigid techniques, are responsible for the physiological changes in respiratory mechanics. Flexible bronchoscopy (FB) can induce a decrease of the cross-sectional area of the upper airways, the generation of a negative tracheal pressure during the suctioning maneuvers, and upper airway collapse. These alterations can lead to hypoxemia and, when lung parenchyma is already compromised by an underlying pathologic condition, to the development of respiratory failure or worsening of such preexisting condition. Moreover, FB requires topical anesthesia and eventually sedation, which can modify the critical closing pressure of the upper airways, inducing their collapse, and affect the breathing pattern and/or the respiratory drive. The use of conventional oxygen therapy (COT) is appropriate to reduce transitory procedural hypoxemia. However, the inspired oxygen fraction cannot be predicted and might not be enough in severe cases. High-flow nasal cannula oxygen therapy (HFNCOT) has been introduced as an alternative for oxygen support during FB. HFNCOT can ensure a more stable Fraction of Inspired Oxygen (FiO2) than COT, generate positive airway pressures in the nasopharynx, reduce the dead space in the upper airways, increase the alveolar ventilation, and decrease the resistive breathing effort, thus reducing the upper airway resistance. The application of continuous positive airway pressure (CPAP) has also been adopted since it results in positive pressure throughout the entire breathing cycle, thereby recruiting lung atelectatic regions, reducing venous admixture, and decreasing the patient’s inspiratory effort. The application of noninvasive ventilation can facilitate the performance of FB in patients with severe respiratory failure through its beneficial effects: it prevents alveolar collapse or recruits closed alveoli, thus augmenting ventilation; it decreases the work of breathing and improves lung mechanics, thereby ameliorating gas exchange and hypoxemia.