Background <p>Ciprofol is increasingly used for endoscopic sedation due to its reduced injection pain, but evidence regarding its safety when combined with etomidate in elderly patients remains limited. This study evaluated the efficacy and safety of ciprofol–etomidate compared with ciprofol alone and propofol–etomidate in elderly patients undergoing upper gastrointestinal endoscopy.</p> Methods <p>In this randomized controlled trial, 402 patients aged ≥ 60 years scheduled for upper gastrointestinal endoscopy were assigned to one of three groups: ciprofol–etomidate (EC: 0.3&#xa0;mg/kg ciprofol + 0.12&#xa0;mg/kg etomidate), ciprofol (C: 0.4&#xa0;mg/kg) alone, or propofol–etomidate (EP: 1.2&#xa0;mg/kg propofol + 0.12&#xa0;mg/kg etomidate). All patients received remifentanil 0.3&#xa0;µg/kg before sedation. The primary outcome was hypotension incidence. Secondary outcomes included sedation success, vital signs, and other adverse events.</p> Results <p>Hypotension incidence differed significantly among groups (EC: 64.5%, C: 80.9%, EP: 75.2%; <i>p</i> = 0.008), with a lower rate in the EC group versus the C group (<i>p</i> = 0.003). Injection pain was rare in both EC (0.7%) and C (1.5%) groups compared with EP (9.0%; <i>p</i> &lt; 0.001). Induction time was longer in EC and C groups than in EP. Recovery and discharge times were prolonged in the C group compared with EP. Other adverse events, including bradycardia, hypoxemia, nausea, vomiting, dizziness, and tremors, did not differ significantly among groups.</p> Conclusions <p>The combination of ciprofol and etomidate offers effective sedation, reducing hypotension compared with ciprofol alone and injection pain compared with propofol–etomidate, and may therefore represent a safer alternative for elderly patients undergoing upper gastrointestinal endoscopy.</p> Trial registration <p>Chinese Clinical Trial Registry, ChiCTR2300077770 (date: 20/11/2023).</p>