Background: Endoscopic papillectomy (EP) carries a potential risk of procedure-related adverse events and incomplete resection. Since hybrid endoscopic submucosal dissection (ESD) had been established as an alternative option for relatively large and difficult gastrointestinal tumors, we evaluated a novel EP with hybrid ESD (hybrid ESD-EP) for curative safe margin in this proof-of-concept study. Methods: A total of eight cases who underwent hybrid ESD-EP between 2018 and 2020 were identified from our prospectively maintained database. Hybrid ESD-EP involved a (sub)circumferential incision with partial submucosal dissection, and subsequent snare resection of ampullary tumors, which was performed by two endoscopists with expertise in ESD or endoscopic retrograde cholangiopancreatography. Demographic data and clinicopathological outcomes were retrospectively evaluated. Results: En bloc resection was achieved by hybrid ESD-EP in all eight cases, with the median procedure time of 112 (range: 65–170) minutes. The median diameters of the resected specimens and tumors were 18 and 12 mm, respectively. All lateral margins were clear, whereas vertical margin was uncertain in three (38%), resulting in the complete resection rate of 63%. Postoperative bleeding and pancreatitis developed in each one (13%). No tumor recurrence was observed even in those cases with uncertain vertical margin, after a median follow-up of 244 (range, 97–678) days. Conclusions: Hybrid ESD-EP seems to be feasible and promising in ensuring the lateral resection margin. However, further investigations, especially to secure the vertical margin and to shorten the procedure time, should be required.