He was professor of chemistry at the University of California San Diego from 1960 to 1972, and previously at Johns Hopkins University, Columbia University and the University of Chicago. He was married to Nobel Prize-winning physicist Maria Goeppert Mayer from 1930 until her death in 1972. He went to work with James Franck in Göttingen, Germany in 1929, where he met Maria, a student of Max Born. Joseph Mayer was president of the American Physical Society from 1973 to 1975.
He developed the cluster expansion method and Mayer-McMillan solution theory.