Histoplasmosis is one of the most common endemic mycoses affecting immunocompromised individuals in the United States and Latin America. Involvement of the central nervous system carries higher mortality rates and worse prognosis, given its resemblance to stroke, vasculitis, and meningitis of other etiologies. The diagnosis is challenging, due to its subtle clinical presentation and the poor sensitivity of the cerebrospinal fluid culture. Herein the authors present a case of a middle-aged man with HIV, who presented with intermittent headaches exacerbated by an oculomotor nerve palsy, concerning for acute stroke. A diagnosis of central nervous system histoplasmosis was made, and his neurological deficits subsided after initiation of treatment. The stroke-like syndrome in this scenario may be secondary to granulomatous vasculitis of small caliber cerebral blood vessels. Histoplasmosis of the central nervous system remains a challenging diagnosis, which requires a high index of suspicion by the clinician for an early institution of therapy in order to improve outcomes.