Cicerone joined the University of Michigan as a research scientist, later holding faculty positions in electrical and computer engineering from 1971 to 1978. In 1978 he moved to the Scripps Institution of Oceanography at UC San Diego as a research chemist. He was appointed senior scientist and director of the Atmospheric Chemistry Division at the National Center for Atmospheric Research in Boulder, Colorado, in 1980. He held this position until 1989 when he joined the University of California, Irvine (UCI), as professor of earth system science (having founded the department) and chaired the Department of Earth System Science from 1989 to 1994, when he became Dean of Physical Sciences. Cicerone was recognized on the citation for the 1995 Nobel Prize in chemistry awarded to colleague F. Sherwood Rowland. In 1998 he became the fourth Chancellor of UCI.   Ralph Cicerone held the position of Chancellor of UC Irvine until 2005, when he left to be President of the National Academy of Sciences. He retired as NAS President in June 2016.
In 2001, while chancellor of UCI, Cicerone led an academy panel, commissioned by George W. Bush, tasked with reporting to him on climate change. The panel concluded unequivocally that "greenhouse gases are accumulating in Earth's atmosphere as a result of human activities, causing surface air temperatures and subsurface ocean temperatures to rise."
Cicerone was a member of the USA Science and Engineering Festivals Advisory Board, a Foreign Member of the Royal Society,  Academia Sinica, the American Academy of Arts and Sciences, the American Philosophical Society, the Accademia Nazionale dei Lincei, the Russian Academy of Sciences, the Korean Academy of Science and Technology. He also served as president of the American Geophysical Union, the worlds largest society of earth scientists.