Background <p>For the patients at high-risk of aspiration, general anesthesia may increase the risk of aspiration, while local pharyngeal anesthesia may cause extreme discomfort and even failure of gastroscopy. In this study, we tested the efficacy and safety of conscious analgesia with oxycodone in these patients.</p> Methods <p>In this prospective, randomized, double-blind, parallel-controlled trial, the patients were randomly assigned to either the oxycodone group (group O) or the 0.9% saline group (group C). Before the gastroscope insertion, group O received oxycodone (0.05&#xa0;mg/kg), while group C received an equivalent volume of 0.9% normal saline. In cases where initial gastroscope insertion failed, a rescue dose of propofol (0.5&#xa0;mg/kg) was administered. The success rate of the first gastroscopy placement, the number of gastroscope insertion and rescue propofol, total consumption of propofol, duration of the procedure, patient tolerance, perioperative adverse events, the satisfaction of patients and endoscopists were compared.</p> Results <p>A total of 175 patients were recruited, and no patient experienced aspiration. The success rate of initial gastroscope insertion and the satisfaction of patients and endoscopists in group O were higher than those in group C (<i>P</i> &lt; 0.001). The number of gastroscope insertion, rescue times and total consumption of propofol, duration of the procedure, the behavioral pain scale non-intubated (BPS-NI) at the time of initial gastroscope insertion, intraoperative retching, limb movement, and tachycardia in group O were significantly lower than those in group C (all <i>P</i> &lt; 0.001).</p> Conclusion <p>Conscious analgesia with oxycodone could help some patients at high risk of aspiration to complete the gastroscopy effectively and safely.</p> Trial registration <p>Registered in the Chinese Clinical Trial Registry (ChiCTR-2100053142 ) on November 13, 2021.</p>