Trauma to the skull causing injury to the middle meningeal artery, middle meningeal vein, or dural venous sinuses is responsible for most cases of epidural hemorrhage (EDH). Spontaneous EDH is a rare entity in clinical practice. Common causes include sinusitis, coagulation abnormalities, dural metastasis, and Langerhans cell histiocytosis. Isolated nontraumatic EDH is an exceedingly rare complication of sickle cell disease (SCD). We report a case of spontaneous EDH in a patient with SCD and review the world literature regarding this rare entity. A 20-year-old African American female with sickle cell disease presented with vaso-occlusive crisis. About 24 hours after hospital admission, the patient had sudden deterioration of her mental status. An emergent CT scan of the head revealed a large right-sided frontoparietal epidural hematoma with midline shift, subfalcine, and uncal herniation. The patient underwent emergent hematoma evacuation but died 24 hours after surgery.