Introduction <p>Oliceridine is a novel G-protein selective µ-agonist that has been reported to provide better analgesia and safety than conventional opioids. The purpose of this study is to explore the efficacy and safety of oliceridine combined with propofol-etomidate(PE) sedation in geriatric outpatients undergoing painless gastroscopy.</p> Methods <p>This prospective, single-center, double-blinded, randomized controlled trial will be conducted at a tertiary A hospital and will enroll one hundred twelve geriatric outpatients undergoing painless gastroscopy. Eligible participants will be randomly assigned to either the experimental group or the control group.The experimental group will receive oliceridine combined with PE sedation, while the control group will receive dezocine combined with PE sedation.The primary efficacy and safety outcomes will be the use of PE sedation and the occurrence of adverse events during painless gastroscopy. Secondary outcomes will include hemodynamic parameters during painless gastroscopy and adverse events during the post-anaesthesia care unit (PACU) stay. Exploratory outcomes will encompass gastroscopy time; time to awakening in the PACU; length of stay in the PACU; pain score, sedation score, and modified Aldrete score at PACU discharge; endoscopist satisfaction; patient satisfaction; and the readmission rate.</p> Disscusion <p>We hypothesize that oliceridine combined with PE sedation will provide more effective analgesia with improved safety. The findings of this trial will furnish helpful clinical evidence and guidance for the novel selection of analgesics for geriatric outpatients undergoing painless gastroscopy.</p> Trial registration <p>ChiCTR2500098774.</p>