Background <p>Hypoxia is one of the most common adverse events of sedated gastrointestinal (GI) endoscopy. It can cause coronary ischemia and permanent nervous system damage, potentially leading to death if not promptly addressed. This study aims to examine the efficacy and safety of the COMBO (capnography monitoring bite block oxygenation) endoscopy oropharyngeal airway in patients undergoing sedated GI endoscopy.</p> Methods <p>A multicenter randomized, open-label, two-arm parallel-group superiority clinical trial with an active comparator will be conducted to evaluate the impact of the COMBO endoscopy oropharyngeal airway on the incidence of hypoxia. This study will include patients (<i>n</i> = 1200) undergoing GI endoscopy under propofol sedation. Written informed consent will be obtained from them. The participants (patients undergoing elective upper gastrointestinal endoscopic surgery, ≥ 18 years old and ≤ 60 years old, American Society of Anesthesiologists Grade I–II, expected inspection time ≤ 45&#xa0;min) will be randomly assigned to a conventional nasal cannula (Arm 1)or the COMBO endoscopy oropharyngeal airway group (Arm 2). The intervention group will be administered the COMBO endoscopy oropharyngeal airway correspondingly. The primary objective is the incidence of hypoxia (75% ≤ SpO₂ &lt; 90% for &lt; 60 s). The secondary objective is the incidence rate of subclinical hypoxia (90% ≤ SpO₂ &lt; 95%) and severe hypoxia (SpO₂ &lt; 75% or 75% ≤ SpO₂ &lt; 90% for ≥ 60 s), and other adverse events.</p> Discussion <p>The COMBO endoscopy oropharyngeal airway is a novel method for oxygenation and airway management. This study is aimed at investigating whether the COMBO endoscopy oropharyngeal airway can reduce the incidence of hypoxia in patients during gastrointestinal endoscopy under sedation with propofol. If successful, our proposal could play a pivotal role that represents a significant advancement in airway management in preventing hypoxemia during GI endoscopy under propofol sedation.</p> Trial registration <p>ClinicalTrials.gov NCT06081647, registered on October 15, 2023.</p>