Background: Structural disorders of the hypopharynx can lead to dysphagia-related morbidity. Endoscopic therapy in this area, for example, myotomy for Zenker's diverticulum (ZD), has traditionally been performed under general anesthesia (GA). We have developed a two-stage sedation process, which is used along with high-flow nasal oxygen therapy (HFNOT) to facilitate endoscopic hypopharyngeal procedures. Methods: In this prospective, single-center study, patients undergoing endoscopic procedures between June 2016 and March 2018 were included. All endoscopies were performed with propofol and/or remifentanil and supported with HFNOT. In patients with ZD, the diverticulum and stomach were cleared of debris under conscious sedation to reduce the risk of aspiration, before sedation was deepened to facilitate myotomy. Sedation-related adverse events were recorded. Results: A total of 50 patients were included for analysis (mean age of 71.1, range 31–93; 58% male); 48% were categorized as American Society of Anesthesiologists (ASA) Grade III and 6% as Grade IV. The median procedure time was 20 min. Of patients, 83% were sedated with both propofol and remifentanil using a target-controlled infusion under specialist anesthetic supervision. Sedation-related adverse events included transient hypotension (38%), bradycardia (8%), and hypoxia (8%). No procedures were abandoned due to complications, and no patients required conversion to GA. Patients achieved full postprocedure recovery from sedation after a median duration of 5 min. Conclusions: HFNOT is a useful adjunct to two-stage sedation, which can enable high-risk patients to safely undergo deep sedation during hypopharyngeal endoscopic procedures.