Spontaneous cerebrospinal fluid leak with meningoencephaloceles in sphenoid sinus lateral recess is challenging. Transnasal visualization of this area is difficult, especially when large pneumatization is present. External approaches to this region involve aggressive surgery and are often associated with significant morbidity. The aim of this study is to assess the real effectiveness of a modification of the endoscopic endonasal approach for their management. This is a prospective case series study and was conducted at Otolaryngology department, Ain Shams University Hospitals, Cairo, Egypt. Seven patients with spontaneous cerebrospinal fluid leak with meningoencephaloceles in the sphenoid sinus lateral recess were included. Diagnosis was confirmed by: analysis for beta-2 transferrin and imaging. They were managed with endoscopic endonasal retrograde trans-sphenoid approach described in this study with multilayered reconstruction of the defect. Mean age of our patients was 40.14 ± 8.35 years; mean BMI was 36.37 ± 2.59 kg/m. Primary empty sella was present and osteodural defect was identified in superior wall of sphenoid sinus lateral recess with punched out and regular smooth edges. Mean intra-cranial pressure was (26.42 ± 3.87 mmHO) and size of defect was less than 10 mm, mean 7.85 ± 1.34. Mean-operative time was 169.28 ± 21.87 min. The mean hospital stay was 7.42 ± 1.39 days. No cerebrospinal fluid leak recurrences were observed during follow-up period that ranged from 37 to 48 months. Endoscopic endonasal retrograde trans-sphenoid approach provides a wide, safe, and direct route to the management of sphenoid sinus lateral recess cerebrospinal fluid leak.