Treating lumbar disease at the intervertebal foramina is controversial because we lack an approach providing sufficient exposure and preserving spinal stability. The primary objective of this study was to investigate the feasibility of the transforaminal fenestration (TFF) approach for treating lumbar disease involving the intervertebal foramina.In the anatomic study of 30 adult cadaveric lumbar spine specimens, the TFF approach was used from L1 to S1. The scope of resection was measured manually and on 3D CT images. 3D CT images of the lumbar spine of 31 adult patients were collected, and the scope of resection needed during the TFF approach was defined and measured from L1 to S1. In total, 30 patients (14 men) with lumbar FLDH underwent microendoscopic discectomy (MED) via the TFF approach. The results were evaluated with visual analog scale (VAS), Oswestry Disability Index (ODI), Short Form-36 survey (SF-36), and the MacNab scale.In cadavers, the TFF approach provided sufficient exposure to the posterolateral aspect of the disc and the exiting nerve root at all segments. At L1 to L4, a relatively small part of the isthmus and facet joint was resected; at L4 to S1, a relatively large part of the isthmus and facet joint was resected, so luniform fenestration was needed to preserve a more inferior articular process and continuity of the isthmus. Treatment with MED via the TFF approach was successful in the 30 patients with significantly relieved of symptom after operation. In total, 24 patients were followed for a mean of 24 months. The VAS, ODI, SF-36 physical component, and mental component summary scores at the final follow-up improved significantly compared with preoperative data (P < .05), and excellent results were obtained in 19 patients and good results in 6 according to the Macnab scale.The TFF approach can provide sufficient exposure to the lumbar intervertebal foramina with preservation of stability and can be used effectively with MED to treat lumbar FLDH.