The macroscopic anatomy of the brain of the American Plains Buffalo (Bison bison bison) is detailed herein for the first time. Many features vary significantly from most previously described ungulate species including its large size, fissural pattern of the cerebral hemispheres and well developed insular cortex. The midbrain, particularly the tectum, is outstanding: the superior colliculi appear to be the largest reported for any mammal and occupy most of the dorsal midbrain by surface area and volume estimates. The cerebellum is small relative to the total brain volume, a peculiarity reported elsewhere for other ungulates. Morphometric criteria further indicate the brain of bison is highly specialized. Drawing from various lines of evidence, it is suggested that the anatomical uniqueness of the present day bison brain may represent a vestige of the past, remaining largely unchanged over a broad expanse of geologic time.