The Oriental Institute has undertaken projects in every part of the ancient Near East, including the Nile Valley, Mesopotamia, Persia, parts of the Ottoman Empire, and the lands of the Bible. Institute scholars also maintain research projects in Chicago, such as dictionaries and lexicons of ancient Akkadian, Hittite, Demotic, Egyptian, and Sumerian.

It was in the Near East that the earliest civilizations of the ancient world arose, beginning as a heterogeneous group of cultures that began to crystallize into urban societies of literate states and empires around 3000 B.C. in both Egypt and Mesopotamia. Among the achievements of the geographically and chronologically diverse cultures that arose in this area are the domestication of wild grains (including wheat and barley) and animals (such as sheep, goats, and cattle), and the invention of writing and the alphabet.