Clough's first academic position was as an assistant professor at Duke University; his next position took him to Stanford University, where he became a full professor. In 1982, he was hired by Virginia Tech as a professor of civil engineering and coordinator of the geotechnical programs. In 1990, Clough became dean of the Virginia Tech College of Engineering and in 1993, he moved to provost and vice president for academic affairs at the University of Washington.

In 1994, Clough became the first Tech alumnus to serve as the President of the Institute, succeeding John Patrick Crecine, and was in office during the 1996 Summer Olympics. In 1998, he separated the Ivan Allen College of Management, Policy, and International Affairs into the Ivan Allen College of Liberal Arts and returned the College of Management to "College" status. During his tenure, research expenditures increased from $212 million to $425 million, computers became required for all students, enrollment increased from 13,000 to 18,000 students, Tech received the Hesburgh Award, and Tech's U.S. News & World Report rankings steadily improved.

His tenure was especially focused on a dramatic expansion of the Institute; since he took office, over $900 million has been spent on expanding or improving the campus. These projects include the completion of several west campus dorms, the manufacturing complex, 10th and Home, Technology Square, The Biomedical Complex, the Student Center renovation, the expanded 5th Street Bridge, the Georgia Tech Aquatic Center's renovation into the Campus Recreation Center, the new Health Center, the Klaus Advanced Computing Building, and the (currently under construction) Nanotechnology Research Center. He also spearheaded a revamped Undergraduate Research Opportunities Program (UROP), and the creation of an International Plan. The students of Georgia Tech affectionately dubbed him "G Wayne" during his presidency in accordance with the expansion and growth he encouraged in urban Atlanta.

On March 15, 2008, Clough announced in an email to students and staff that he would be stepping down as President on July 1, 2008 after nearly fourteen years as President. He left to serve as the Secretary of the Smithsonian Institution.

Clough was named 12th Secretary of the Smithsonian Institution on March 15, 2008 at a press conference held at the Smithsonian Castle. Clough assumed office July 1, 2008. Since beginning his new post, Clough has already made plans to digitize the Museum's collections, and offer more intensive K-12 educational programming.