John Jeffries joined the University of Virginia law faculty two years after earning his law degree in 1973. His primary research and teaching interests are civil rights, federal courts, criminal law and constitutional law. Jeffries has co-authored casebooks in civil rights, federal courts and criminal law and has published a variety of articles in those fields. He also wrote a biography of Justice Lewis F. Powell, Jr. In 1986, Jeffries was appointed the inaugural Emerson Spies Professor of Law, a position created to honor a long-time teacher and former dean. Jeffries has also held a variety of other academic appointments, including the Arnold H. Leon Professorship. 

He served as academic associate dean from 1994 to 1999. In the fall semester of 1999, he was acting dean during the sabbatical of Dean Robert Scott. He became dean in the fall of 2001 and served until June 2008. In 2017 he received the Thomas Jefferson Award for excellence in scholarship; the awards are the highest honor given to members of the University community. From August 2018-January 2021 he was senior vice president for advancement at UVA. He now serves as counselor to UVA President Jim Ryan. During law school, Jeffries served as editor-in-chief of the Virginia Law Review. He received the Z Award for the highest academic average and the Woods Prize for the outstanding graduate. Immediately after graduation, he clerked for Justice Lewis F. Powell, Jr., before serving in the U.S. Army as a second lieutenant.