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South American native ungulates include extinct taxa that evolved within the geographical context given by the isolation of South America during most of the Cenozoic. The ungulates (orders Notoungulata, Litopterna and Astrapotheria) of the Santa Cruz Formation (late Early Miocene) are particularly interesting for paleobiological studies due to their diversity, richness and quality of preservation of the specimens. The body mass estimation of extinct species is one of the basic biological attributes for paleobiological reconstructions. The most common way to estimate body mass from fossils is using linear regression. Here, we used geometric morphometric techniques in order to estimate their body mass. We used regressions based on centroid size of 3D craniomandibular landmark configurations, including extant ungulates (their size and ecological relatives). Cases were weighted to maximize the taxonomic evenness. A broad body size range was recorded. The highest predictive power is obtained with those functions derived from the highest taxonomic and ecological diversity. The highest taxonomic richness corresponds to masses below 100 kg. Among Notoungulata, typotheres (Hegetotheriidae + Interatheriidae) vary from 1 to less than 10 kg, while the smaller toxodontid reached 100 kg and the larger 500 kg. Litoptern proterotheriid body masses vary from 10 to 50 kg, and macraucheniids surpass 100 kg. The astrapotheres (Astrapotheria) reached (or even surpassed) 1000 kg, being the only megamammal in the Santacrucian ungulate assemblage.