Scedosporium apiospermum is an opportunistic fungus that, although rare, has emerged as an etiological agent of severe infections, often with difficult diagnosis and treatment. One clinical manifestation of invasive fungal infection caused by S. apiospermum is central nervous system involvement, especially in immunocompromised patients such as those with diabetes mellitus. The neurotropism of this fungus is significant and is associated with contiguous spread and hematogenous dissemination. The reported case is a 70-year-old male, a bricklayer, hypertensive, diabetic with a history of recurrent sinusitis, who developed severe frontal headache and retro-ocular pain in the left eye for 2 months; antibiotic therapy had been taken irregularly. After 15 days, despite treatment, he progressed to ptosis and amaurosis of the left eye, unintentional weight loss, lower limb paresis, and decreased level of consciousness. He was referred to a tertiary hospital after another visit to an urgent care unit and underwent brain MRI, which showed partial opacification of the sphenoid sinuses with surrounding bony sclerosis consistent with chronic sinusitis, associated with multifocal bony erosions, small organized extra-axial frontobasal bilateral fluid collections in the anterior interhemispheric fissure and suprasellar cisterns, with involvement of the left optic nerve (orbital apex syndrome). Surgery was performed with biopsy and specimen collection, and nasal secretion culture grew S. apiospermum. Given invasive meningoencephalitis, combined antibiotic therapy plus voriconazole was initiated. Despite treatment, the patient developed infectious complications associated with mechanical ventilation and bloodstream infection, and died 60 days after hospital admission. Patients with diabetes mellitus have an increased risk of fungal infections due to metabolic and immunological changes associated with the disease, as chronic hyperglycemia may reduce T-cell response, neutrophil function, and humoral immunity. This report highlights the importance of this etiological agent to support clinical reasoning regarding differential diagnoses.