Protypotherium is an extinct genus of notoungulate mammals native to South America during the Oligocene and Miocene epochs. A number of closely related animals date back further, to the Eocene. Fossils of Protypotherium have been found in the Deseadan Fray Bentos Formation of Uruguay, Muyu Huasi and Nazareno Formations of Bolivia, Cura-Mallín and Río Frías Formations of Chile, and Santa Cruz, Salicas, Ituzaingó, Aisol, Cerro Azul, Cerro Bandera, Cerro Boleadoras, Chichinales, Sarmiento and Collón Curá Formations of Argentina.

Notoungulata is an extinct order of ungulates that inhabited South America from the early Paleocene to the end of the Pleistocene, living from approximately 61 million to 11,000 years ago. Notoungulates were morphologically diverse, with forms resembling animals as disparate as rabbits and rhinoceroses. Notoungulata are the largest group of South American native ungulates, with over 150 genera in 14 families having been described, divided into two major subgroupings, Typotheria and Toxodontia. Notoungulates first diversified during the Eocene. Their diversity declined from the late Neogene onwards, with only the large toxodontids persisting until the end of the Pleistocene, perishing as part of the Late Pleistocene megafauna extinctions along with most other large mammals across the Americas. Collagen sequence analysis suggests that notoungulates are closely related to litopterns, another group of South American ungulates, and their closest living relatives being perissodactyls, including rhinoceroses, tapirs and equines as part of the clade Panperissodactyla. However their relationships to other South American ungulates are uncertain. Several groups of notoungulates separately evolved ever-growing cheek teeth.