We report the case of a 50-year-old woman with long-standing, steroid-dependent ulcerative colitis who received neoadjuvant chemotherapy followed by subtotal gastrectomy with Roux-en-Y reconstruction for gastric adenocarcinoma. After 4 weeks, she presented to the emergency department with abdominal pain and clinical sepsis; computed tomography (CT) demonstrated free intraperitoneal air with a large perianastomotic fluid collection. She underwent re-operation for suspected anastomotic dehiscence, but no anastomotic or mural defect was identified intraoperatively. The postoperative course was complicated by laparotomy wound dehiscence with bile-stained secretions, managed with negative pressure wound therapy (NPWT). A subsequent CT scan with water-soluble oral contrast showed no extraluminal contrast leakage. Because symptoms and wound output persisted one month after the second surgery despite conservative management, endoscopic evaluation of the anastomoses and duodenal stump was undertaken under general anesthesia using single-balloon enteroscopy (SBE) with CO₂ insufflation and continuous fluoroscopic guidance, permitting retrograde access to the duodenal stump via the afferent limb. On endoscopic inspection, two discrete defects, each approximately 8 mm, were identified at opposite edges of the stump suture line; endoluminal fluoroscopic contrast injection opacified both tracts, confirming an enterocutaneous fistulous communication. Margin preparation was performed with argon plasma coagulation (APC) in pulsed mode at 30 W. Fibrin glue was then delivered via a 23-gauge needle as submucosal injections in a multi-quadrant fashion around each orifice (2 mL per quadrant) and intratract, for a total of 20 mL. To maintain apposition and support re-epithelialization, six 11-mm through-the-scope (TTS) clips were placed across the defects. The procedure was uneventful. Drain output declined rapidly and reached zero within 72 hours; CT scan at day 7 showed no residual leakage. Oral intake was resumed on day 8, NPWT was discontinued, and the patient was discharged without additional intervention. At 180-day follow-up, she remained asymptomatic with no recurrence. In the setting of Roux-en-Y anatomy and late duodenal stump fistula—where device delivery and effectiveness may limit conventional endoscopic suturing systems, this combined SBE-guided approach (APC margin freshening, targeted submucosal and intratract fibrin sealant, and adjunctive TTS clipping) proved feasible, safe, and promptly effective. Patient selection is key: controlled sepsis and small-to-moderate defects favored success, allowing a minimally invasive rescue that may obviate re-operation while preserving the surgical reconstruction.