Zepeda is a professor of linguistics at the University of Arizona and is well known for her efforts in the preservation of her native language and promotion literacy in it. She is also known for her work as a consultant and advocate on behalf of a number of American indigenous languages. Her book A Papago Grammar is the standard textbook used to teach the Tohono O'odham language. She was a student of MITlinguistics professor Ken Hale.
In 1999, Zepeda received a MacArthur Fellowship. She is the Poet Laureate of Tucson, Arizona. For several years, she continues to serve as editor for numerous journals and book series. In 2012, her book was banned by Tucson schools.