Peutz-Jeghers syndrome (PJS) is an autosomal-dominant genetic disorder characterized by the formation of hamartomatous polyps in the gastrointestinal tract. These polyps result in significant morbidity due to adverse events (AEs) including intestinal obstruction, bleeding, and malignancy. The aim of this study was to describe the role of device-assisted enteroscopy (DAE) in monitoring and prophylactic polypectomy within the small bowel. Electronic medical records were surveyed to identify all DAE procedures performed in patients with PJS at three US referral centers between January 1, 2007 and January 1, 2020. Individual charts were reviewed to collect and analyze specific data points. Primary end points included AEs associated with DAE-related polypectomy and the rate of laparotomy in PJS patients prior to, and following, index DAE. Secondary data points included patient characteristics, procedural details, and size/location/distribution of small bowel hamartomas. Twenty-three patients met our inclusion criteria. Of these, 18 (75%) had previously undergone small bowel surgery prior to index DAE. Between 2007 and 2020, 46 DAEs were performed in these patients with an average of one exam every 2.5 years. A total of 131 polypectomies were performed with an AE rate of 1.5%. None of our cohort required emergent surgery related to AEs of small bowel hamartomas over 336 years of aggregated follow-up. Endoscopic management of small bowel polyps in patients with PJS using DAE is an effective strategy for prophylactic removal of hamartomas. DAE surveillance and endoscopic polypectomy is safe and may decrease the need for repeated laparotomy in patients with PJS.