[1] The genus name Mesomys derives from the two ancient greek words μέσος (mésos), meaning "middle of, between", and μῦς (mûs), meaning "mouse, rat".

[2][3] It refers to the fact that these rodents — literally the "middle mouse" — were considered an intermediate form between the genus Loncheres and the genus Echinomys, both of which are now known to be synonyms of Echimys.

[4][5] Mesomys is a member of the Echimyini clade of arboreal Echimyidae rodents.

[6] The closest relative of Mesomys is Lonchothrix, reflecting the fact that these taxa have once been classified in the Eumysopinae,[1] a subfamily now recognized as an artificial assemblage.

[7] These two genera share phylogenetic affinities with several taxa and clades: (i) Echimys, Phyllomys, Makalata, Pattonomys, and Toromys ; (ii) the bamboo rats Dactylomys, Olallamys, Kannabateomys together with Diplomys and Santamartamys ; and (iii) Isothrix.