We herein describe a case of a 54-year-old woman who presented with inappropriate secretion of antidiuretic hormone, diplopia, weakness in the left leg, and bladder and rectum disturbances. Imaging studies of the brain revealed a suprasellar tumor that extended into the posterior portion of the sella turcica. Cerebrospinal fluid contained lymphoma cells that expressed CD10, CD19, CD38, and CD138, but not CD5, CD20, or surface/cytoplasmic immunoglobulins. Fluorescence in situ hybridization using a series of probes showed that lymphoma cells concurrently carried “triple-hit” rearrangements involving MYC, BCL2, and BCL6, and their partners not only in the immunoglobulin heavy chain gene, but also in the non-immunoglobulin gene loci. The patient failed to respond to chemoradiotherapy and died of disease progression shortly thereafter. A postmortem examination revealed lymphoma infiltration into the hypothalamus, frontal lobe, choroid plexus, dura mater, and spinal nerves, and lymphoma tissues exhibited high-grade B-cell lymphoma histopathology. This case represents a rare presentation of triple-hit lymphoma, which was initially confined to the central nervous system (CNS). The development of new and effective agents for double/triple-hit lymphoma associated with CNS disease is a significant unmet medical need.