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Background: Digestive tract reconstruction is required after the surgical resection of a colorectal malignant tumor. Some patients may have concomitant anastomotic complications, such as anastomotic stenosis with fistula (ASF), postoperatively. Therefore, we evaluated the efficacy and safety of endoscopic fully covered self-expandable metal stent and homemade vacuum sponge-assisted drainage (FSEM-HVSD) for the treatment of ASF following the radical resection of colorectal cancer. Methods: Patients treated with FESM-HVSD were prospectively analyzed and followed up for ASF following colorectal cancer treatment in our medical center from 2017 to 2021 for the observation and evaluation of its safety and efficacy. Results: Fifteen patients with a mean age of 55.80 ± 11.08 years were included. Nine patients (60%) underwent protective ileostomy. All 15 patients were treated with endoscopic FSEM-HVSD. The median time from the index operation to the initiation of FSEM-HVSD was 80 ± 20.34 days in patients who underwent protective ileostomy versus 11.4 ± 4.4 days in those who did not. The average number of endoscopic treatments per patient was 5.70 ± 1.25 times. The mean length of hospital stay was 27.60 ± 4.43 days. FSEM-HVSD treatment was successful in 13 patients, and no patients had any complications. The follow-up time was 1 year. Twelve of 15 (80%) patients achieved prolonged clinical success after FSEM-HVSD treatment, 1 experienced anastomotic tumor recurrence and underwent surgery again, and 1 patient required balloon dilation for anastomotic stenosis recurrence. Conclusions: FSEM-HVSD is an effective, safe, and minimally invasive treatment for ASF following colorectal cancer treatment. This technique could be the preferred treatment strategy for patients with ASF. [ABSTRACT FROM AUTHOR]