The study of the cranial endocast provides valuable information to understand the behavior of an organism because it coordinates sensory information and motor functions. In this work, we describe for the first time the anatomy of the encephalon of an early Miocene pan-octodontoid caviomorph rodent (Prospaniomys priscus Ameghino, 1902) found in the Argentinean Patagonia, based on a virtual 3D endocast. This fossil rodent has an endocast morphology here considered ancestral for Pan-Octodontoidea and other South American caviomorph lineages, i.e., an encephalon with anteroposteriorly aligned elements, mesencephalon dorsally exposed, well-developed vermis of the cerebellum, and rhombic cerebral hemispheres with well-developed temporal lobes. Prospaniomys Ameghino, 1902 also has relatively small olfactory bulbs, large paraflocculi of the cerebellum, and low endocranial volume and degree of neocorticalization. Its encephalization quotient is low compared with Paleogene North American and European noncaviomorph rodents, but slightly higher than in several late early and late Miocene caviomorphs. Paleoneurological anatomical information supports the hypothesis that Prospaniomys was a generalist caviomorph rodent with terrestrial habits and enhanced low-frequency auditory specializations. The scarce paleoneurological information indicates that several endocast characters in caviomorph rodents could change with ecological pressures. This work sheds light on the anatomy and evolution of several paleoneurological aspects of this particular group of South American rodents.