Introduction: Isolated sphenoid sinus lesions cause symptoms such as headache and visual abnormalities. Endoscopic examination and imaging modalities are mandatory to reach a diagnosis. Objectives: To validate the importance of a direct trans-nasal trans-sphenoid endoscopic approach as a minimally invasive surgical strategy in isolated sphenoid sinus and sellar lesions. Patients & Methods. There are 21 patients in our study, collected over 2 years period. we recorded all patients with isolated sphenoid sinus and sellar lesions. These patients were scheduled for a direct trans-nasal trans-sphenoid endoscopic approach for surgical management. Pituitary adenomas affect ten of them, and isolated sphenoid sinus lesions affect eleven. Complete medical history was taken, as well as general examination and local examination including full ENT examination including endoscopic examination, neurological examination, and ophthalmological examination. Routine laboratory investigations, hormonal assay (in patients with pituitary tumors), and radiological evaluation were done. Results: We faced 21 patients 10 of them had pituitary adenomas and 11 of them had isolated sphenoid sinus lesions. 7 patients had non-secretory pituitary adenomas, 3 patients had secretory adenomas, 4 patients had sphenoid sinus mucoceles, 2 patients had spheno-choanal polyps, 2 patients had isolated sphenoid sinus fungal sinusitis, one patient had a granulomatous lesion, one patient had a neoplastic lesion (squamous cell carcinoma), and one patient had unilateral isolated sphenoiditis. Conclusion: Direct trans-nasal trans-sphenoid endoscopic approach is the preferred option for optimal surgical management of patients with isolated sphenoid sinus and sellar lesions.