Millis joined the Department of Economics at the University of Chicago in the fall of 1916 as an assistant professor of economics. He was appointed chair of the department in 1928, and became Professor Emeritus in 1938 at the age of 65. He became associated with the "institutional economics" school, whose foremost proponents were then primarily teaching at the University of Chicago.van Overtveldt, The Chicago School: How the University of Chicago Assembled the Thinkers Who Revolutionized Economics and Business, 2007, p. 128. Between 1938 and 1945, he and Royal E. Montgomery of Cornell University co-wrote a three-volume study titled The Economics of Labor. At the time of his death, a group of prominent economists called it "the most authoritative and comprehensive analysis of modern labor economics for the period covered." He followed this with How Collective Bargaining Works in 1942, a text which set the pattern for case studies in the field of industrial relations.
