Chicago is the major U.S. city that is NOT located along the Mississippi River.

Chicago, Illinois, is a prominent U.S. city located on the shores of Lake Michigan, quite distant from the Mississippi River. Although it serves as a vital center for transportation and commerce, it lacks a direct link to the river. In comparison, cities such as Baton Rouge, St. Louis, and Memphis flourish along the Mississippi, capitalizing on its resources for trade and cultural importance. Chicago's distinct location shapes its economic pursuits, including shipping and tourism, but does not engage with the Mississippi River.