Background and Objectives: Brain imaging studies in pediatric patients with headaches often reveal inflammation of the sphenoid sinus. When we encounter patients presenting with headaches without respiratory symptoms, determining the causal relationship between isolated sphenoid sinusitis observed in brain imaging studies and headache is challenging. This study aims to evaluate the clinical characteristics of pediatric patients with headaches and isolated sphenoid sinusitis identified by brain imaging studies and to determine the effects of antibiotics on headache relief. Materials and Methods: Among patients aged <18 years with headaches, those in whom isolated sphenoid sinusitis was observed on brain imaging were included. Their medical records were retrospectively reviewed to evaluate their clinical characteristics and outcomes. Based on antibiotic and analgesic effects, the included patients were categorized into acute bacterial sinusitis (BS) and non-BS groups, and clinical data were compared between the two groups. Results: Brain imaging studies were performed for 1751 patients, and 205 (11.7%) and 41 (2.3%) patients demonstrated sinusitis and isolated sphenoid sinusitis, respectively. For the 41 patients with isolated sphenoid sinusitis, migraine with or without aura (58.5%) was the most frequent type of headache. Throbbing pain (34.1%) occurred most frequently, and the temporal area (51.2%) was the most common location of headache. Nausea/vomiting (56.1%) was the most common accompanying symptom, followed by ocular symptoms (34.1%). Only one (2.4%) patient complained of neurologic symptoms. Headache improved in 26 (63.4%) patients, with improvement without antibiotic therapy in 19 (46.3%) patients. The acute BS and non-BS groups demonstrated comparable characteristics, except for a higher frequency of ocular symptoms in the acute BS group than in the non-BS group (p = 0.044). Conclusions: Isolated sphenoid sinusitis was rarely identified in pediatric patients with headache examined using brain imaging studies. Considering the clinical characteristics and antibiotic effects, early intensive antibiotic therapy cannot be prioritized.