The interior design of Comfort Hotel Grand Central is grounded both in the history of the building (parts of which are heritage-protected) and in a utilitarian aesthetic designed to appeal to the creative class. Varying greatly in shape and size, the building's 170 hotel rooms are furnished in a spare, urban style highlighted with lived-in, heirloom elements.

Artwork by Ariel McMillion appears in 158 rooms, and 57 bathroom niches, as well as in elevators and public spaces, and on signs throughout the building.