Although writing systems have been studied for centuries by linguists, Gelb is widely regarded as the first scientific practitioner of the study of scripts, and coined the term grammatology to refer to the study of writing systems. In A Study of Writing (1952), he suggested that scripts evolve in a single direction, from logographic scripts to syllabaries to alphabets. This historical typology has been criticized as overly simplistic, forcing the data to fit the model and ignoring exceptional cases. Yet, despite more recent refinements of the typology by Peter T. Daniels and others, Gelb's rigorous study of the properties of different kinds of writing system was pioneering and innovative. Gelb believed that the Maya hieroglyphs did not qualify as true writing capable of representing language, which has now been disproven following the decipherment of the Maya script.
Gelb's work in Assyriology focused on publishing editions of Akkadian texts and a grammar and dictionary of Old Akkadian. He became editor of the Chicago Assyrian Dictionary in 1947 and continued work on the project until his death. His other important works include works on Mesopotamian land tenure and sales, metrology, and other aspects of economic and social history.