To (i) introduce the technical notes of a novel full-endoscopic foraminotomy with a large endoscopic trephine for the treatment of severe degenerative lumbar foraminal stenosis at L S level; (ii) assess the primary clinical outcomes of this technique; (iii) compare the effectiveness of this full-endoscopic foraminotomy technique and other previous techniques for lumbar foraminal stenosis. From January 2019 to August 2019, a retrospective study of L S severe degenerative lumbar foraminal stenosis was performed in our center. All patients who were diagnosed with severe foraminal stenosis at L S level and failed conservative treatment for at least 6 weeks were identified. Patients with segmental instability or other coexisting contraindications were excluded. A total of 21 patients were enrolled in the study. All patients were treated by full-endoscopic foraminotomy using large endoscopic trephine. The visual analogue scale (VAS) and Oswestry disability index (ODI) were evaluated preoperatively and at 1, 3, 6 months, and 1 year after the surgery, and the modified MacNab criteria were used to evaluate clinical outcomes at the last follow-up. There were 10 males and 11 females with a mean age of 66.38 ± 9.51 years. Five patients had a history of lumbar surgery. The mean operative time was 63.57 ± 25.74 min. The mean follow-up time was 13.29 ± 1.38 months. The mean postoperative hospital stay time was 1.29 ± 0.56 days. The mean preoperative VAS score significantly decreased from 7.38 ± 1.02 to 2.76 ± 1.09 (t = 19.759, P < 0.01), 2.25 ± 1.02 (t = 21.508, P < 0.01), 1.60 ± 1.05 (t = 31.812, P < 0.01), and 1.45 ± 1.10 (t = 25.156, P < 0.01) at 1 month, 3 months, 6 months, and 1 year after the operation. The mean preoperative ODI score significantly decreased from 64.66% ± 4.91% to 30.69% ± 4.59% (t = 33.724, P < 0.01), 29.44% ± 4.50% (t = 32.117, P < 0.01), 24.22% ± 4.14% (t = 33.951, P < 0.01), and 22.44% ± 4.94% (t = 30.241, P < 0.01) at 1 month, 3 months, 6 months, and 1 year after the operation. At the last follow-up, 19 patients (90.48%) got excellent or good outcomes. One patient suffered postoperative dysesthesia, and the symptoms were controlled by conversion treatment. One patient took revision surgery due to the incomplete decompression. There were no other major complications. Percutaneous endoscopic decompression is minimally invasive spine surgery. However, the application of endoscopic decompression for L S foraminal stenosis is relatively difficult due to the high iliac crest and narrow foramen. Full-endoscopic foraminotomy with the large endoscopic trephine is an effective and safe technique for the treatment of degenerative lumbar foraminal stenosis.