Background <p>Ciprofol (CIP) for procedural sedation and analgesia (PSA) for painless gastrointestinal endoscopy (GE) can cause respiratory or cardiovascular complications. The literature suggests that intravenous (IV) lidocaine infusion can alleviate visceral pain and enhance humans’ ventilator response to CO₂. Therefore, it was hypothesized that IV lidocaine could reduce the CIP dose for painless GE and improve recovery time.</p> Methods <p>This randomized placebo-controlled trial included 40 patients undergoing GE. After CIP titration for unconsciousness, patients in group L were given IV lidocaine (1.5&#xa0;mg/kg bolus dose, then a 2&#xa0;mg/kg/h continuous infusion); the same volume saline as placebo was given for N group patients. The primary endpoint was the required CIP dose. Secondary endpoints were: endoscopic examination time, awakening time, post-anesthesia care unit (PACU) discharge time, pain and fatigue after awakening, adverse events, and endoscopist’s and patient’s satisfaction.</p> Results <p>Both cohorts had comparable demographic characteristics. Group L’s CIP consumption was decreased by 23.0% than the N group (47.38 ± 7.45&#xa0;mg vs. 61.50 ± 9.44&#xa0;mg, respectively, <i>p</i> &lt; 0.001). Awakening time (<i>P</i>=0.002), PACU discharge time (<i>P</i> &lt; 0.001), pain (<i>P</i> = 0.008), and fatigue (<i>P</i> = 0.004) after awakening were also reduced in group L. Furthermore, group L had higher satisfaction scores than group N (<i>P</i> = 0.017). No marked difference was identified in the incidence of unfavorable effects (<i>P</i> &gt; 0.05 for all).</p> Conclusions <p>Lidocaine IV infusion caused a 23.0% reduction in CIP requirements during GE. Furthermore, post-endoscopic pain and fatigue were also improved, thus suggesting that lidocaine is an efficient therapeutic option.</p> Trial registration <p>This trial has been submitted to the Chinese Clinical Trial Registry (registration number: ChiCTR2300069868, registration date: 28/03/2023).</p>