Non-invasive ampullary tumors, may be treated with endoscopic (EA) or surgical ampullectomy (SA). However, evidence on the morbidity of these techniques remains limited. This pilot study aimed to assess and compare morbidity of EA and SA. Patients undergoing EA or SA for non-invasive ampullary tumors were retrospectively analyzed and compared. Outcomes were postoperative complications graded with Clavien Classification and Comprehensive Complication Index (CCI), and length of stay (LoS). A review of the literature was performed to propose an evidence-based algorithm to treat ampullary tumors. A total of 11 EA and 19 SA were identified and analyzed. EA was associated with shorter intervention (51 vs. 191 min, p < 0.001) and decreased blood loss (0 vs. 100 mL, p < 0.001). Postoperative complications were more frequent after surgery compared to endoscopy (9% vs. 68%, p = 0.002). Surgical patients showed a higher CCI (0 vs. 8.7, p < 0.001). LoS was reduced in patients undergoing endoscopy (0 vs. 14 days, p < 0.001), with comparable readmissions rates (p = 0.126). Necessity of subsequent treatment was more frequent after endoscopic, compared to SA (5 vs. 1, p = 0.016). EA was associated with lower morbidity than SA and appeared as an appropriate first-line treatment for non-invasive ampullary tumors. SA remains a valuable alternative after EA failure.