She is Professor of Linguistics at the University of California at Santa Barbara. Mithun has worked on a wide variety of languages from a wide variety of language families, but specializes in Native American languages. She began her career with extensive fieldwork on Iroquoian languages, especially Mohawk, Cayuga, and Tuscarora, She has also worked in California on Central Pomo and the Chumashan languages, on Central Alaskan Yup'ik, and on the Austronesian language Kapampangan.
Mithun compiled a comprehensive overview of Native American languages in The Languages of Native North America. A review on the Linguist List describes the work as "an excellent book to have as a reference" and as containing "an incredible amount of information and illustrative data." The work is a bipartite reference organized firstly by grammatical categories (including categories that are particularly widespread in North America, such as polysynthesis), and secondly by family. She has taught at many institutions around the world, including Georgetown, La Trobe, Rice, Stanford, SUNY Albany, Amsterdam, Cagliari, Berkeley, Hamburg, UIUC, UNM, Wake Forest, and Yale.
She was the founding president of the Society for Linguistic Anthropology in 1983. From 1999 to 2003 she was president of the Association for Linguistic Typology.