Isolated sphenoid sinus disease (ISSD) is an uncommon entity and may present with non-specific symptoms. As sphenoid sinus is located adjacent to vital structures, a diseased sphenoid sinus can potentially lead to devastating complications such as cranial neuropathies, cavernous sinus thrombosis and intracranial abscess. Herein, we report a case series of three patients who presented with different localization of headache as their main symptom. Endoscopic nasal assessment showed abnormal nasal cavity findings with mucosal thickening and soft tissue mass occupying the sphenoid sinus revealed by computed tomography (CT) scan. All the sphenoid sinuses were drained via endoscopic approach. Post operatively, antibiotics or anti-fungal were given, however, these three cases displayed the possible variation in severity of this disease. Case 1 had an uncomplicated inflammatory disease of the sphenoid sinus, which is of bacterial origin, while the other two cases had fungal infection. Case 2 achieved disease stability with anti-fungal treatment, but Case 3 had a serious complication after treatment with permanent vision loss. A patient who presents with atypical headache, not responsive to analgesia should be investigated promptly with nasal endoscopic examination and radiological imaging for isolated sphenoid sinus disease to avoid devastating complications.