The Mylodontinae from the late Pleistocene (Lujanian Stage/Age) of Argentina, represented by Lestodon armatus, Mylodon darwinii, and Glossotherium robustum, are known from numerous remains, whereas early and middle Pleistocene Mylodontinae are less well characterized owing to insufficient material. In this work, we describe a new genus and species of Mylodontinae from the Ensenadan Stage/Age based on a cranium and comparisons with South and North American Mylodontinae. The new genus is similar to the taxon Mylodon darwinii, but the presence of plesiomorphic characteristics support a more primitive status for this novel sloth. The addition of this new taxon, Archaeomylodon sampedrinensis, gen. et sp. nov., increases the diversity of Mylodontinae during the middle Pleistocene. This new mylodontine in the middle Pleistocene is an important reference point for interpretations of increasing body size in South American Mylodontinae during the Pliocene–Pleistocene. These changes in body size may have been influenced by the arrival of Holarctic immigrants to South America.