After graduating from Cambridge University, he worked in the Department of Applied Mathematics and Theoretical Physics (DAMTP) at the University of Cambridge from 1962–1969, progressing from senior assistant in research, to assistant director of research, to university lecturer. In 1964, he introduced the Bretherton equation in applied mathematics. From 1969–1974, he was associated with the Johns Hopkins University, first as a professor in the Department of Earth & Planetary Sciences, and then as chief scientist at the Chesapeake Bay Institute.
From 1973 to 1980, Bretherton was president of the University Corporation for Atmospheric Research in Boulder, Colorado. He was also director of the National Center for Atmospheric Research nearly concurrently, from 1974–1980. In 1980, he decided to return to scientific research studies, remaining at NCAR as a senior scientist. During that time he authored over 60 scientific papers.
Bretherton was director of the Space Science and Engineering Center at the graduate school of the University of Wisconsin, Madison from 1988–1999. During that time the center "expanded to add global change studies and management of climate data".
Bretherton has received a number of honors and awards from institutions in both the UK and the US. In 1960 he received the Smiths Prize from the University of Cambridge; in 1960–1962, he was a Research Fellow at Trinity College, Cambridge, and in 1962, he was a Fellow at King's College in Cambridge. In 1970, he was given the Buchan Prize from the Royal Meteorological Society, and in 1971, he received the World Meteorological Organization, Research Award, Area IV. The American Meteorological Society Meisinger Award and the American Meteorological Jule G. Charney Award were given to Dr. Bretherton in 1972 and 1982, respectively.
With Professor Francis Bretherton as SSEC director from 1988-1999, the Center expanded to add global change studies and management of climate data.