Background <p>Optimal respiratory management under deep sedation remains a most concerning safety challenge for pediatric dental treatment due to its shared oral cavity. High-flow nasal oxygenation has been found to be advantageous in certain short-duration pediatric procedures and examinations. Our study aimed to further explore its clinical feasibility in preschool-aged pediatric dental treatment under deep intravenous sedation of prolonged and more complex procedures.</p> Methods <p>This study involved twenty pediatric patients scheduled for elective dental treatment with anticipated operation time of 60–120&#xa0;min under deep sedation. Sedative/anesthetic agents, oxygenation management and perioperative monitoring were performed by qualified anesthesiologists. IV insertion was conducted after the child was calmed with intranasal dexmedetomidine or under general anesthesia with mask inhalation of sevoflurane. During dental treatment, oxygen administration was provided with the HFNO device with a 2.0&#xa0;L/kg/min gas flow rate and an FiO₂ of 1.0. Depth of sedation was maintained by propofol with a target-controlled infusion system. Perioperative pulse oximetry, respiratory status, remedial maneuvers and adverse effects were recorded in detail.</p> Results <p>All included children successfully completed dental treatment under deep sedation. The average operation time was 74&#xa0;min. None of the participants experienced any desaturation and no related complications were reported in our observation and 24&#xa0;h follow-up.</p> Conclusions <p>Based on our initial experience, HFNO could provide ideal oxygenation in preschool-aged pediatric dental treatment under deep sedation without clinically observed complications and adverse events. Whereas the provider qualification, strict training of HFNO device, proper use and close monitoring must be emphasized.</p> Trial registration <p>The study was registered at ClinicalTrials.gov (No. NCT05762692) and first posted on 10/03/2023.</p>