High-flow oxygen therapy (HFOT) is a respiratory support system, through which high flows of humidified and heated gas are delivered to hypoxemic patients. Several mechanisms explain how HFOT improves arterial blood gases and enhances patients’ comfort. Some mechanisms are well understood, but others are still unclear and under investigation. HFOT is an interesting oxygen-delivery modality in perioperative medicine that has many clinical applications in the intensive care unit (ICU) and the operating room (OR). The purpose of this article was to review the literature for a comprehensive understanding of HFOT in the perioperative period, as well as its uses in procedural sedation. This review will focus on the HFOT definition, its physiological benefits, and their mechanisms, its clinical uses in anesthesia, and when it is contraindicated.