After graduating from Queen's University with undergraduate and master's degrees, Clayton completed a Ph.D. in 1955 at the California Institute of Technology, where he was mentored by geochemist Samuel Epstein. His first academic appointment was at Penn State University. In 1958, he joined the chemistry faculty at the University of Chicago, where he took over the laboratory of Nobel Prize winner Harold Urey. From 1961 to his retirement in 2001, he held joint appointments in the chemistry and geophysical sciences departments. He directed the Enrico Fermi Institute at the university from 1998 to 2001.
