Liodon nepaeolicus was named by Cope (1874). Its type specimen is AMNH 1565, a partial skull, and it is a 3D body fossil. Its type locality is 0.5 mi south of Solomon River, which is in a Coniacian/Santonian marine shale in the Niobrara Formation of Kansas. It is the type species of Tylosaurus.

It was recombined as Tylosaurus nepaeolicus by Merriam (1894), Hay (1902), Hay (1930), Russell (1967), Bell et al. (2013), Fanti et al. (2014), Driscoll et al. (2019).