Background <p>Electrocoagulation with an electrosurgical knife is the traditional approach to achieve haemostasis during endoscopic submucosal dissection (ESD), as bleeding may obscure the operative field and increase the risks of muscle injury and perforation.</p> Aims <p>The aim of this study was to assess the efficacy and safety of the sequential injection-electrocoagulation procedure during ESD.</p> Methods <p>In this randomized controlled trial, 69 patients undergoing upper gastrointestinal ESD were randomized to either the control group (traditional electrocoagulation) or the experimental group (“Sequential injection-electrocoagulation” method) from September 2023 to June 2024. Two endoscopists scored the visibility of each bleeding point from 1 (undetectable) to 4 (easily detectable).</p> Results <p>The median time to haemostasis at each bleeding point was 17 (11–23) seconds in the experimental group and 22 (14.5–41) seconds in the control group (<i>P</i> &lt; 0.001). The visibility scores were significantly higher in the experimental group than in the control group (3.24 ± 0.63 vs. 2.82 ± 0.57) (<i>P</i> &lt; 0.001). Muscle injuries occurred more frequently in the control group (<i>P</i> = 0.003). Unfortunately, there was one case of perforation in the control group caused by haemostasis.</p> Conclusion <p>The sequential injection-electrocoagulation strategy shortened the time to hemostasis during ESD, improved the visibility of bleeding points, and minimized the risks of muscle injury and perforation.</p> Graphical Abstract <p></p>