McDonough was born in Hong Kong the son of an American Seagram's executive, and trained at Dartmouth College and Yale University. In 1981 McDonough founded his practice, and his first major commission was the 1984 Environmental Defense Fund Headquarters. McDonough's practice is currently located in Charlottesville, Virginia, with a small office in San Francisco, California. McDonough moved his practice from New York City to Charlottesville in 1994, when he was appointed as the Dean of the School of Architecture at the University of Virginia. He relinquished this position in 1999 to focus on expanding his professional practice.