Caviomorphs constitute a monophyletic group, representative of the oldest rodent radiation in South America. Since the Oligocene they have contributed importantly to the fossil communities of South American mammals. Today, caviomorphs display a diverse array of locomotor and feeding behaviors, occupying a wide range of habitats in which they consume a variety of food items. In this contribution, we analyze species of Santacrucian caviomorphs from a morphofunctional perspective in the context of extant caviomorph behavioral diversity, in order to evaluate their paleobiology and its paleoenvironmental significance. Body masses based on Santacrucian specimens were estimated by applying published equations. Reconstructions were made of areas of origin and insertion of the main masticatory muscles following the muscular pattern observed in living caviomorphs. On this basis, functional analyses of the masticatory apparatus were performed. Major postcranial features in extant caviomorphs identified as functionally associated with different locomotor habits were used as a model to evaluate the functional significance of the postcranial features in Santacrucian species. Santacrucian caviomorphs examined show the range of body mass from small- to relatively large-sized living caviomorphs. The porcupine Steiromys duplicatus and the dasyproctid Neoreomys australis present features that indicate a diet of harder and more abrasive food items than those consumed by living Neotropical phylogenetically related species. Features of the masticatory apparatus of the eocardiid Eocardia fissa are compatible with a wide feeding behavior, including abrasive food. Steiromys duplicatus was a semi-arboreal form, which did not achieve the degree of specialization that is seen in the Neotropical extant Coendou. Eocardia fissa was a cursorial agile rodent, similar to living Pediolagus salinicola. Neoreomys australis was a cursorial species, more similar to living Agouti paca than to Dasyprocta species. Santacrucian caviomorphs could have lived in an environment like the Cerrado biome, showing differential utilization of food resources and locomotor behaviors.