It has been proposed that some or all of the members of this group form a clade, named Meridiungulata, though the relationships of South American ungulates remain largely unresolved.

Though most SANUs lived in South America, astrapotheres and litopterns are known from Eocene aged deposits in the Antarctic Peninsula[1] and the notoungulate Mixotoxodon spread as far north as what is now Texas during the Pleistocene as part of the Great American Biotic Interchange.

Meridiungulata might have originated in South America from a North American condylarth ancestor,[3] and they may be members of the clade Laurasiatheria, related to other ungulates, including artiodactyls and perissodactyls.

[6] Molecular sequence data from both collagen[7][8] and mitochondrial DNA[9] supports that litopterns and notoungulates are most closely related to Perissodactyla (the group containing equids, rhinoceroses, and tapirs) among living mammals, as part of the clade Panperissodactyla, making them true ungulates, which has also been supported by some analyses of morphology.

[1] Litopterns and notoungulates are the only South American ungulates to have gone extinct recently enough for molecular data to be available, so the relationships of astrapotheres, pyrotheres, and xenungulates must be determined based on morphology alone.

[1] The causes of the decline are unclear, but may be due to climatic change,[19] or competition/predation from new arrivals from North America as part of the Great American interchange.