Background <p>Cipepofol, a novel anesthetic agent, may offer advantages for older patients undergoing painless digestive endoscopy. This study evaluated the safety and efficacy of this approach compared to a combination of etomidate and propofol (EP).</p> Methods <p>In this single-center, double-blind, randomized, non-inferiority trial, 120 older patients(aged 65–90 years) undergoing painless gastroscopy or colonoscopy were randomized to receive either cipepofol (0.3–0.4&#xa0;mg/kg; <i>n</i> = 60) or EP (1:1 ratio, 0.15–0.2 mL/kg; <i>n</i> = 60). Primary outcomes included sedation duration. Secondary outcomes assessed sedation success, recovery time, discharge readiness, adverse events, and hemodynamic stability.</p> Results <p>All patients achieved successful sedation (100%). Initial sedation duration was comparable between the cipepofol and EP groups (8.73 [5.10, 10.18] vs. 7.41 [5.35, 9.09] minutes; <i>p</i> = 0.165). Recovery times were similar (5.49 [3.51, 7.62] vs. 4.86 [3.36, 8.86] minutes; <i>p</i> = 0.819), while discharge readiness was faster in the cipepofol group (1.67 [0.78, 2.38] vs. 2.96 [1.21, 7.23] minutes; <i>p</i> = 0.002). Adverse events, including hypotension, bradycardia, and hypoxia, were comparable. Injection pain occurred only in the EP group (5%).</p> Conclusion <p>In older patients undergoing painless digestive endoscopy, cipepofol is non-inferior to the etomidate-propofol combination in sedation duration and safety. It also shares the characteristic of stable hemodynamics and offers advantages, including reduced injection pain and a shorter time to meet discharge criteria, providing a simplified choice for clinical practice.</p> Trial registration <p>ChiCTR2400088889, Date of Registration: 2024-08-28, <a href="https://www.chictr.org.cn/showproj.html?proj=212632">https://www.chictr.org.cn/showproj.html?proj=212632</a>.</p>