Fossil remains of extinct terrestrial sloths have been discovered in numerous localities throughout the Americas, but knowledge of these animals remains poor in the tropical latitudes in comparison with the austral ones. Even where Pliocene mylodontine sloths are known from North and South America, well-preserved craniodental remains are extremely rare, hindering reliable assessment of their taxonomic assignment and phylogenetic affinities. Here, new craniodental remains of Simomylodon uccasamamensis, from the latest Miocene–Pliocene of the Bolivian Altiplano, are described and compared with those of other Neogene Mylodontinae from South and North America. The resulting morphological observations, combined with morphometric analyses, permit reliable differentiation among these moderate-sized Miocene–Pliocene mylodontids. Simomylodon uccasamamensis appears to be the smallest Pliocene mylodontine, and it is closely related phylogenetically to the late Miocene species Pleurolestodon acutidens. Simomylodon uccasamamensis is also an endemic taxon of the Andean highlands during the Pliocene, with a continuous chronological range extending throughout the Montehermosan, Chapdamalalan and (early) Marplatan South American Land Mammal Ages. This terrestrial sloth may have found its ideal ecological conditions in the Bolivian Altiplano, during a span of time falling between the important South American Late Miocene–Pliocene faunal turnover and the Great American Biotic Interchange around the Pliocene–Pleistocene transition.