Abstract Background and study aims The MANTIS Clip (Boston Scientific) is a novel anchor pronged clip designed to enhance tissue grasping and facilitate the closure of defects in the gastrointestinal tract. This study evaluates the feasibility and effectiveness of the MANTIS Clip for closing mucosal defects following colorectal endoscopic submucosal dissection (C-ESD). Patients and methods A retrospective single-center study was conducted on patients who underwent C-ESD with MANTIS Clip closure from May 2023 to April 2024. The primary outcome measured was the complete closure success rate. Secondary outcomes included defect size, sustained closure rate, closure time, number of clips used, adverse events (AEs), and hospital stay duration. Results The MANTIS Clip was used in 52 cases. The complete closure rate was 98.1% (51/52), with a sustained closure rate of 96.1% (49/51). The median closed defect size was 32 mm, with the largest being 62 mm. The median closure time was 8 minutes. Typically, one MANTIS Clip per defect was used, with only one lesion requiring two clips. The median number of additional clips used was seven. AEs included one case of bleeding (1.9%) and one case of post-ESD coagulation syndrome (1.9%), both managed without extending hospital stays. The median C-reactive protein level on the first day post-ESD was 0.35 mg/dL and the median hospital stay was 5 days. Conclusions The MANTIS Clip is effective and practical for mucosal defect closure post-C-ESD, demonstrating high success and sustained closure rates with minimal complications. Future multicenter randomized trials are needed to further assess its efficacy and safety.