<b><i>Background:</i></b> Post-polypectomy coagulation syndrome (PECS) is a well-known adverse event after endoscopic polypectomy for colorectal lesions. To date, there are no standardized guidelines for the antimicrobial prophylaxis. The aim of this meta-analysis is to evaluate the usefulness of antibiotics in patients undergoing endoscopic mucosal or submucosal resections. <b><i>Methods:</i></b> A comprehensive literature search of PubMed, MEDLINE, EMBASE, and Web of Science databases was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies investigating the role of prophylactic antibiotic administration in reducing the PECS after endoscopic polypectomy were considered. The terms used to search were (“antimicrobial”OR”antibiotics”OR”prophylaxis”OR”prophylactic”) AND (“resection”OR”polypectomy”OR”dissection”) AND (“endoscopic”OR”mucosal”OR”submucosal”) AND (“colon”OR”colorectal”OR”colonic”OR”rectum”). Data of included studies were collected and analysed. <b><i>Results:</i></b> The literature search revealed 262 articles, 3 of whom were randomized trials and one was a retrospective study. Patients included were 850 (548 treated with antibiotics and 302 received no treatment). The overall incidence rate was 2.4 and 19.9% in treatment and control groups, respectively. The pooled analysis showed a reduction of 83% of postoperative events in the antibiotics group (relative risk 0.181; 95% CI 0.100–0.326, <i>p</i> &#x3c; 0.001). <b><i>Conclusions:</i></b> In our meta-analysis, the antibiotic prophylaxis showed a positive effect in reducing the incidence of postoperative adverse events other than perforation and bleeding in patients treated with endoscopic mucosal resection and endoscopic submucosal dissection for colorectal lesions. Despite the low-level of evidence of this meta-analysis, the antibiotic prophylaxis should be taken into account. Further multicenter, large-sample, randomized controlled studies are needed to confirm our results and to evaluate whether specific subgroups of patients could actually benefit from an antibiotic prophylaxis.