Objective To conduct a systematic review and meta-analysis comparing the therapeutic efficacy of endoscopic full-thickness resection (EFTR) and endoscopic submucosal dissection (ESD) for colorectal lesions. Methods A comprehensive search of PubMed, Web of science, Cochrane Library and Embase databases until October 1, 2025, supplemented by manual reference screening, identified studies comparing EFTR and ESD. Studies were selected based on predefined inclusion/exclusion criteria, with methodological quality assessed using standardized tools. Meta-analysis was performed using RevMan 5.4, calculating pooled odds ratios (OR) and standardized mean differences (SMD) with 95% confidence intervals. Results Five studies involving 570 patients were analyzed. EFTR and ESD showed comparable en bloc resection rates (OR = 2.59, 95%CI 0.38 ∼ 17.77, P = 0.33) and R0 resection rates (OR = 1.73, 95%CI 0.71 ∼ 4.20, P = 0.23). EFTR demonstrated superior safety profiles with significantly lower postoperative perforation risk (OR = 0.13, 95%CI 0.05 ∼ 0.37, P < 0.001), reduced post-polypectomy syndrome incidence (OR = 0.23, 95%CI 0.08 ∼ 0.68, P = 0.008), and shorter procedure time (SMD=-1.97, 95%CI -2.95 ∼ -0.99, P < 0.001). No significant differences were observed in postoperative bleeding (OR = 0.96, 95%CI 0.31 ∼ 2.94, P = 0.94) or lesion recurrence rates (OR = 2.47, 95%CI 0.76 ∼ 8.01, P = 0.13). Conclusions In summary, EFTR yields favorable short-term outcomes for selected small or refractory colorectal lesions, particularly non-lifting or recurrent lesions, whereas ESD remains essential for larger superficial colorectal neoplasia requiring en bloc resection. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO , identifier CRD42024534672.