A unique and diverse albeit phylogenetically restricted mammal fauna is known from the Caribbean region. The region—specifically, all islands in the Caribbean Sea (except for small islets close to the continental mainland) and the Bahamas, Turks and Caicos Islands, and Barbados, which are not in the Caribbean Sea but biogeographically belong to the same Caribbean bioregion—has been home to several families found nowhere else, but much of this diversity is now extinct.

The bat faunas of much of the Caribbean show similarities that led to the proposal of a distinct Caribbean faunal region, bounded by "Koopman's Line". This region excludes several of the region's islands, including the Grenadines, Grenada, Trinidad, Tobago, and other islands near the American mainland, such as Margarita, Isla Escudo de Veraguas, Rosario Islands, Cozumel, and the Florida Keys. The faunas of islands outside Koopman's Line are similar to those of the adjacent mainland, though usually smaller; in contrast, the region inside Koopman's Line harbors relatively few species shared with the mainland and many of its species belong to endemic genera, subfamilies, and even families.

Excluding bats, nearly 90% of the mammals of the Caribbean faunal region have gone extinct since the late Pleistocene, including all the sloths and monkeys, the unique insectivore Nesophontes, two of four species of solenodon, and a variety of rodents including all giant hutias, leaving only a few hutia species extant. Most of these species (the sloths, monkeys, and caviomorph rodents) were of South American origin. The oryzomyine rodents were of ultimately of Nearctic origin, but except for those on Jamaica would also have reached the Caribbean via South America. The origin(s) of the Caribbean eulipotyphlans are uncertain.

Non-flying mammals of Cenozoic origin must have colonized the Caribbean islands by some combination of rafting and/or use of a "land span" (a temporary land bridge connecting South America with one or more off-shelf islands). Colonization of a series of islands can occur either by an iterative rafting process ("island-hopping"), or by colonization of a large ancestral island which is then subdivided by into smaller islands by subsequent geologic or sea level changes (island-island vicariance). The restricted, unbalanced nature of the Caribbean mammal fauna implies that rafting was part of the overall process. This is consistent with the fact that megalonychid sloths, platyrrhine monkeys and caviomorph rodents have all shown a capacity for this type of dispersal (in their colonization of North America from South America prior to the formation of the Isthmus of Panama in the first case, and of South America from Africa in latter two cases). These three groups are known in the Caribbean from fossils as old as the early Oligocene, early Miocene and early Miocene, respectively. Rafting is also consistent with the prevailing flow of oceanic currents from South America towards the islands.

The large proportion of extinctions can be attributed to the isolated and therefore somewhat less competitive nature of the islands' ecosystems, and to the fact that carnivorans never colonized most of the region. These factors made the islands' native fauna particularly vulnerable to disruption by humans and the invasive species they introduced. The large predator niches of the Caribbean islands were formerly occupied by endemic outsize hawks, falcons, caracaras, teratorns and owls, such as Titanohierax, Gigantohierax, Buteogallus borrasi, Caracara tellustris, Oscaravis olsoni, Ornimegalonyx and Tyto pollens - all of which are now extinct. Cuban crocodiles also have more terrestrial habits than other extant crocodilians.

Opossums (order Didelphimorphia), the largest group of American marsupials, are of limited diversity in the Caribbean. The large opossum Didelphis marsupialis is found on Trinidad and Tobago and in the Windward Islands up to Dominica, being found on Martinique, Saint Lucia, Saint Vincent, Grenada, and the Grenadines of Carriacou, Mustique, and Bequia. At least some of the latter populations may have been introduced by humans. In Central America, it is also found on the islands of Cozumel, Mexico, and Roatán, Honduras. The smaller Marmosa robinsoni is also known from Trinidad, Tobago, Grenada, and Roatán, but the classification of Central American populations of this species is unclear. In addition, Marmosa murina is known from Trinidad and Tobago, Marmosops fuscatus and Chironectes minimus from Trinidad only, and Caluromys philander from Trinidad and the Venezuelan island of Margarita. A related species, Caluromys derbianus, is known from the small Panamanian island of Escudo de Veraguas.

Armadillos (order Cingulata) include about 20 species, mostly in South America. One species, the nine-banded armadillo (Dasypus novemcinctus) is known from Trinidad, Tobago, and Grenada. An unspecified fossil armadillo has been recorded from Bonaire in the ABC Islands.

The order Pilosa includes the sloths and anteaters, about ten species of which survive in Central and South America. Until the middle Holocene, the Greater Antilles and surrounding islands were home to at least as many species of sloths in four or more genera. All of those are now extinct, with many last appearance dates coinciding roughly with the first arrival of humans. The extinct Caribbean sloths were generally more terrestrial than extant sloths, although not exclusively so. Some other pilosans are still found on islands along the margin of the Caribbean.