The most common major adverse event of endoscopic mucosal resection (EMR) is clinically significant post-EMR bleeding (CSPEB), with an incidence of 6%–7% in large lesions. Repeat colonoscopy, blood transfusions, or other interventions are often needed. The associated direct costs are much higher than those of an uncomplicated EMR. In this review, we discuss the aspects related to CSPEB of large nonpedunculated polyps, such as risk factors, predictive models, and prophylactic measures, and we highlight evidence for preventive treatment options and explore new methods for bleeding prophylaxis. We also provide recommendations for steps that can be taken before, during, and after EMR to minimize bleeding risk. Finally, this review proposes future directions to reduce CSPEB incidence.