Introduction <p>Endoscopic submucosal dissection (ESD) offers significant advantages, including the potential for curative resection of early-stage neoplasms. Despite this, the application of ESD for treating duodenal lesions remains sparse, particularly in the Western region. We aim to determine the feasibility of outpatient duodenal ESD from a tertiary referral center experience in the United States.</p> Methods <p>Consecutive patients undergoing duodenal ESD from 2019 to 2024 at a tertiary referral center were included. The primary outcomes were the rate of en-bloc resection and curative resection. The secondary outcomes were the adverse event rate, including perforation or bleeding. Cohorts were compared using Chi-square, Fischer exact test, and logistic regression.</p> Results <p>The study included 37 patients (57% females) with a mean age of 67&#xa0;years (SD: 12). The mean diameter of the lesions was 39.1&#xa0;mm (SD: 27.2), of which 54% (<i>n</i> = 20) were adenomatous lesions followed by 46% (<i>n</i> = 17) neuroendocrine lesions. All cases performed in an outpatient setting. Overall, 81% (<i>n</i> = 30) of lesions were removed by en-bloc resection, with a 67.6% (<i>n</i> = 25) R0 resection rate. Closure was performed in 68% (<i>n</i> = 25) of lesions. The adverse event rate was 5%, with two cases of delayed bleeding reported and no cases of delayed perforation. Mean resection time was 60&#xa0;min (± 39&#xa0;min). No significant difference was noted in en-bloc resection of adenomatous vs neuroendocrine tumors (69.6% vs 100%, <i>P</i> = 0.638) or R0 resection (69.6% vs 64%, <i>P</i> = 0.085), respectively.</p> Conclusion <p>When performed by very experienced endoscopists, duodenal ESD can be performed effectively and safely for non-ampullary duodenal lesions, achieving high en-bloc resection rates with low adverse event rates. Defect closure may help mitigate delayed adverse events, supporting the feasibility of outpatient duodenal ESD.</p>