Nyctitheres are a diverse Paleogene group of insectivorous mammals from Asia, North America, and Europe. Known mostly from their relatively unspecialized tribosphenic dentitions, various taxa currently placed in the family Nyctitheriidae have previously been considered to belong to such disparate extinct eutherian families as Leptictidae and Adapisoriculidae, and some have even been considered to be early bats. Here we describe a large collection of nyctitheres from the late Paleocene (early Clarkforkian) of Big Multi Quarry in Sweetwater County, Wyoming, USA, representing the most diverse faunal assemblage of nyctitheres currently known. Big Multi Quarry is unique among currently known Clarkforkian sites because of its excellent preservation of microvertebrates, including hundreds of specimens belonging to Eulipotyphla, Primatomorpha, Metatheria, and Multituberculata. The Big Multi fauna includes at least eight species of nyctitheres and preserves the earliest known occurrences of the genera Ceutholestes Rose and Gingerich, 1987, and Plagioctenoides Bown, 1979, as well as additional specimens belonging to the species Limaconyssus habrus Gingerich, 1987, and Wyonycteris chalix Gingerich, 1987. New species of nyctitheres from this fauna include: Ceutholestes acerbus, new species; Plagioctenoides cryptos, new species; Plagioctenodon dawsonae, new species; and Plagioctenodon goliath, new species. This large sample of nyctitheres enhances our knowledge of the anatomy of several poorly known taxa including those comprising the subfamily Placentidentinae, for which we provide an emended diagnosis.