Born in Pittsburgh, Pennsylvania, Fowler moved with his family to Lima, Ohio, a steam railroad town, at the age of two. He graduated from the Ohio State University, where he was a member of the Tau Kappa Epsilon fraternity, and received a Ph.D. in nuclear physics at the California Institute of Technology. Although an experimental nuclear Physicist, Fowler's most famous paper was "Synthesis of the Elements in Stars", coauthored with Cambridge cosmologist Fred Hoyle and in collaboration with two young Cambridge astronomers, E. Margaret Burbidge and Geoffrey Burbidge. That 1957 paper in Reviews of Modern Physics categorized most nuclear processes for origin of all but the lightest chemical elements in stars. It is widely known as the BFH paper.

Fowler won the Henry Norris Russell Lectureship of the American Astronomical Society in 1963, the Vetlesen Prize in 1973, the Eddington Medal in 1978, the Bruce Medal of the Astronomical Society of the Pacific in 1979, and the Nobel Prize in Physics in 1983 for his theoretical and experimental studies of the nuclear reactions of importance in the formation of the chemical elements in the universe (shared with Subrahmanyan Chandrasekhar).

Fowler was the doctoral advisor at Caltech for Arthur B. McDonald, who would later go on to win the 2015 Nobel Prize in Physics, and for Donald D. Clayton, who became the leader of the next generation of nuclear astrophysics and who in 2000 was elected Fellow of American Academy of Arts and Sciences.