Neurosurgeons often neglect the sphenoid sinus due to its deep location and difficulties in accessing during surgical interventions. Disease of the sphenoid sinus is difficult to diagnose since its presenting symptoms are difficult to recognize. Moreover, compared with other paranasal sinuses, the sphenoid sinus is considered the most variable air sinus in terms of its degree of pneumatization, number and position of inter-sinus septa, and its relationship with the surrounding anatomical structures. Anatomical variations of the sphenoid sinus are significant from a neurosurgical point of view. Understanding of these variations and its relationships with surrounding structures such as the internal carotid artery, optic nerve, and pituitary gland are clinically relevant to minimize injuries associated with surgical procedures that involve sphenoid sinus. We implemented principles of imaging using computed tomography to elucidate any anatomical variations of the sphenoid sinus in the Ethiopian population. We conducted a prospective study in 200 patients with ages 18–79, who underwent scans of the sphenoid sinus at the Tikur Anbessa Referral Teaching Hospital in 2017–2018. Our findings revealed an incidence of anatomographical variations in terms of pneumatization that varied between 2–50%. These variants include 2% conchal, 25.5% presellar, 50% sellar, and 22.5% postsellar pneumatization. We also demonstrated anatomographic variants in terms of septation, 77.5% single complete septa, 11.5% single incomplete, 10% double septa, and 1% absence of septa. In summary, the sellar pneumatization was found to be the most clinically relevant anatomographic variant among Ethiopians participating in the study, of which 90% were tomographically single septated. These variants must be taken into consideration during trans-sphenoidal surgery and knowledge of the variations has clinical implication in minimizing injuries during invasive surgical procedures involving the sphenoid sinus.