Acute isolated sphenoid sinusitis is a rare disease, and accounts for less than 3% of all sinusitis, especially in young children. Delayed diagnosis or misdiagnosis can occur frequently due to atypical clinical presentations. This can lead to serious complications because of the involvement of anatomically related intracranial structures. Therefore, nasal endoscopy, computed tomography (CT), and magnetic resonance imaging (MRI) are important diagnostic tools to confirm the diagnosis. We report two cases of a previously healthy 6-year-old girl and a 13-year-old boy, whose chief complaints were uncontrolled headache and high fever over 38°C. Physical examination and initial laboratory test results of blood, urine, and cerebrospinal fluid were normal. The diagnosis was made after a brain MRI revealed isolated sphenoid sinusitis. The girl was treated with third generation cephalosporins intravenously. The boy, however, had to undergo an emergent endoscopic sinus surgery as his headache and eyeball-pain symptoms did not resolve by medical treatment alone. Both cases had good outcomes, without neurological sequelae.