Zeppos started his career as a practicing attorney in Washington, D.C.. He joined the faculty of the Vanderbilt Law School in 1987. During his tenure at Vanderbilt, he has held a number of posts, including professor of law, associate dean of the law school, associate provost for academic affairs, vice chancellor for institutional planning and advancement, and, in 2001, provost and vice chancellor for academic affairs. In this last role, he oversaw academics, development, alumni relations, and residential and student life. After Gordon Gee's departure in 2007, he was named interim chancellor. He was named chancellor "suo jure" on March 1, 2008, by the university's Board of Trust. In 2009, he helped lead an expanded financial aid program called Opportunity Vanderbilt that replaced undergraduate need-based loans with grant and scholarship assistance.