He is a well-known researcher and author of over 100 articles, books and patents in the areas of computer security, software engineering, and mathematics.

His first academic appointment was at the University of Wisconsin–Milwaukee, but in 1976 he returned to Georgia Tech as an Associate Professor of Information and Computer Science, where he established a long-term collaboration with Richard Lipton.

[5] In 1987, he moved to Purdue University where he was named Professor of Computer Science and Director of The Software Engineering Research Center.

In 1997, he collaborated with Richard Lipton and Daniel Boneh to create the “Differential Fault Analysis” method of cryptanalysis, leading to a strengthening of existing standards for internet security.

In June 2008, shortly after long-time Georgia Tech President Wayne Clough stepped down to become Secretary of the Smithsonian Institution, DeMillo announced his resignation as Dean of the College of Computing.

[14] In 2011, his book Abelard to Apple: The Fate of American Colleges and Universities [15] was published by MIT press and became the basis for the formation of a center dedicated to experimentation in higher education.

in September 2020, he launched and served as first chair of Georgia Tech's School of Cybersecurity and Privacy, the first academic unit of its kind at a major research university.