Background <p>Colorectal endoscopic submucosal dissection (ESD) enables curative resection but carries a risk of delayed bleeding. The efficacy of prophylactic wound closure remains uncertain. We conducted a systematic review and meta-analysis to evaluate closure versus non-closure and identify high-risk subgroups.</p> Methods <p>Following PRISMA 2020 guidelines, databases were searched to September 2025 for randomized and comparative cohort studies of closure after colorectal ESD. Primary outcome was delayed bleeding; secondary outcomes were perforation and post-ESD coagulation syndrome (PECS). Pooled odds ratios (ORs) were estimated using random-effects models, with subgroup and meta-regression analyses.</p> Results <p>Nine studies (<i>n</i> = 2404) were included. Closure significantly reduced delayed bleeding (OR 0.324, 95% CI 0.172–0.611; <i>I</i>² = 0%). Benefit was greater in large lesions (≥ 3&#xa0;cm: OR 0.293, 95% CI 0.134–0.641) and in studies with higher rectal proportion (≥ 25%: OR 0.306, 95% CI 0.142–0.661). Meta-regression confirmed associations with lesion size (<i>p</i> = 0.0006) and rectal proportion (<i>p</i> = 0.049). Closure did not significantly affect perforation (OR 1.142, 95% CI 0.565–2.309) or PECS (OR 0.723, 95% CI 0.179–2.916).</p> Conclusions <p>Prophylactic closure after colorectal ESD reduces delayed bleeding, particularly in large tumors and rectal lesions, but does not alter perforation or PECS risk. Selective closure in high-risk cases may optimize outcomes.</p> Graphical abstract <p></p>