Extant squirrels exhibit extensive variation in brain size and shape, but published endocranial data for living squirrels are limited, and no study has ever examined brain evolution in Sciuridae from the perspective of the fossil record to understand how this diversity emerged. We describe the first virtual endocast for a fossil sciurid, Cedromus wilsoni, which is known from a complete cranium from Wyoming (Orellan, Oligocene), and make comparisons to a diverse sample of virtual endocasts for living sciurids (N = 20). The virtual endocasts were obtained from high-resolution X-ray micro-computed tomography data. Comparisons were also made with endocasts of extinct ischyromyid rodents, the most primitive rodents known from an endocranial record, which provide the opportunity to study the neuroanatomical changes occurring near the base of Sciuridae. The encephalization quotient of C. wilsoni is higher than that of Ischyromys typus from the same epoch, and falls within the range of modern terrestrial squirrel variation, but below the range of extant scansorial, arboreal and gliding sciurids when using cheek-tooth area for the estimation of body mass. In a principal components analysis, the shape of the endocast of C. wilsoni is found to be intermediate between that of primitive fossil taxa and the modern sample. Cedromus wilsoni has a more expanded neocortical surface area, especially the caudal region of the cerebrum, compared with ischyromyid rodents. Furthermore, C. wilsoni had proportionally larger paraflocculi and a more complex cerebellar morphology compared with ischyromyid rodents. These neurological differences may be associated with improvements in vision, although it is worth noting that the size of the parts of the brain most directly involved with vision [the rostral (superior) colliculi and the primary visual cortex] cannot be directly assessed on endocasts. The changes observed could also relate to balance and limb coordination. Ultimately, the available evidence suggests that early squirrels were more agile and visually oriented animals compared with more primitive rodents, which may relate to the process of becoming arboreal. Extant sciurids have an even more expanded neocortical surface area, while exhibiting proportionally smaller paraflocculi, compared with C. wilsoni. This suggests that the neocortex may continue increasing in size in more recent sciurid rodents in relation to other factors than arboreality. Despite the fact that both Primates and Rodentia exhibit neocortical expansion through time, since the adoption of arboreality preceded major increases in the neocortex in Primates, those neurological changes may be related to different ecological factors, underlining the complexity of the inter-relationship between time and ecology in shaping the brain in even closely related clades.