He studied and published the first analysis of a complete Neanderthal specimen. The fossil discovered in La Chapelle-aux-Saints was an old man, and Boule characterized it as brutish, bent kneed and not a fully erect biped. In an illustration he commissioned, the Neanderthal was characterized as a hairy gorilla-like figure with opposable toes, according to a skeleton which was already distorted with arthritis. As a result, Neanderthals were viewed in subsequent decades as being highly primitive creatures with no direct relation to anatomically modern humans. Later re-evaluations of the La Chapelle-aux-Saints skeleton have roundly discredited Boule's initial work on the specimen.
He was one of the first to argue that eoliths were not manmade.
Boule also expressed some scepticism about the "Piltdown man" discovery — later revealed to be a hoax. As early as 1915, Boule recognized that the jaw belonged to an ape rather than an ancient human. However, the Piltdown forgery has been characterised as providing evidential support for Boule's "branching evolution" conclusions drawn from his Neanderthal research — research which is likewise said to have "prepar[ed] the international community for the appearance of a non-Neanderthal fossil such as Piltdown Man."