The evolution of the brain in rodents has rarely been studied from the perspective of the fossil record. Here we describe the first virtual endocast of a fossil rodent, pertaining to Ischyromys typus (ROMV 1007; Orellan North American Land Mammal Age [NALMA], Nebraska), and form comparisons with partial and complete natural endocasts pertaining to the same genus, and with the virtual endocast of a closely related extant rodent (Sciurus carolinensis; AMNH 258346). These data allow us to formulate the first hypotheses informed by the fossil record concerning changes in brain size and shape through time in rodents, and to make comparisons with other euarchontoglirans, including Primates. Ischyromys exhibits several aspects of brain morphology that can be inferred to be primitive, in part based on their presence in plesiadapiform primates (e.g., exposed midbrain), although variation exists within the genus Ischyromys with respect to the visibility of the inferior colliculi. There is some evidence that neocorticalization occurred in rodents through time but to a lesser degree than in Primates. Arboreality might be linked to increases in the encephalization quotient and specializations related to vision in rodents, which contrasts with the situation in Primates. Finally, Oligocene rodents had smaller olfactory bulbs compared with plesiadapiform primates from the Eocene, meaning that olfaction might have been less critical in the early evolution of rodents. These results show that the evolution of the brain in mammals does not always follow the same evolutionary trajectories and demonstrates the importance of considering ecological factors when looking at brain size.