Central nervous system (CNS) infections, including meningitis, encephalitis, and brain abscess, are rare but time-sensitive emergency department (ED) diagnoses. Patients with CNS infection can present to the ED with nonspecific signs and symptoms, including headache, fever, altered mental status, and behavioral changes. Neuroimaging and CSF fluid analysis can appear benign early in the course of disease. Delaying therapy negatively impacts outcomes, particularly with bacterial meningitis and herpes simplex virus encephalitis. Therefore, diagnosis of CNS infection requires vigilance and a high index of suspicion based on the history and physical examination, which must be confirmed with appropriate imaging and laboratory evaluation.