Recently, underwater endoscopic mucosal resection (UEMR) without submucosal injection was introduced as a new replacement for conventional EMR (CEMR) and was reported to be useful for resecting large colonic polyps. Here, we aimed to assess the efficacy and safety of these two methods by a systematic review and meta-analysis. We comprehensively searched multiple databases until July 2021 to identify randomized controlled trials (RCTs) comparing UEMR with CEMR. The primary outcomes were the proportion of R0 resection and mean procedure time, and the secondary outcomes were the proportion of en bloc resection and all adverse events. Three reviewers independently searched for articles, extracted data, and assessed the risk of bias. We evaluated the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach. This study was registered in www.protocols.io (Protocol Integer ID: 40849). We included six RCTs (1,374 polyps). We judged that a meta-analysis was not available, and the data were summarized narratively for the proportion of R0 resection. Regarding procedure time, UEMR likely resulted in a large reduction (mean difference = -64.3 seconds; 95% confidence interval (CI) = -122.5 to -6.0 seconds; I2 = 86%; moderate certainty of evidence). UEMR likely resulted in a large increase in en bloc resection (odds ratio = 1.85; 95% CI = 1.15 to 2.98; I2 = 60%; moderate certainty of evidence). Percentages of adverse events were 0-17% with CEMR and 0-16% with UEMR. In summary, UEMR might have higher efficacy than CEMR in the endoscopic resection of nonpedunculated colorectal polyps, with likely a large reduction in procedure time.