In 1988, Bowen left Princeton to become president of The Andrew W. Mellon Foundation, where he created a research program to investigate doctoral education, collegiate admissions, independent research libraries, and charitable nonprofits in order to ensure that the Andrew W. Mellon Foundation's grants would be well-informed and more effective.

William Bowen was also partially responsible for JSTOR,[5] the Mellon International Dunhuang Archive, ARTstor, and Ithaka Harbors, Inc. Bowen authored 19 books, including the Grawemeyer Award-winning The Shape of the River: Long-Term Consequences of Considering Race in College and University Admissions (co-authored with Derek Bok).

One of his books, Equity and Excellence in American Higher Education (2005), was coauthored with Eugene M. Tobin and Martin A. Kurzweil.

He also wrote (with James Shulman) The Game of Life: College Sports and Educational Values (Princeton University Press, 2001).

[8] Bowen died on October 20, 2016, fourteen days after his 83rd birthday, in Princeton, New Jersey, United States.