The Oklahoma-born performer's native language is Cherokee, which he spoke until he started primary school at age five. Returning from serving in the Vietnam War, Studi became seriously involved with Native American politics. He joined the American Indian Movement and participated in their 1973 occupation of Wounded Knee, South Dakota. Studi subsequently attended college and helped start a Cherokee newspaper. He also began teaching the Cherokee language professionally before shifting to running his own horse ranch. The late 70s found Studi divorced and bereft of his ranch. Thinking it would be a good way to meet women, he decided to start taking acting lessons.

Studi gained substantial stage experience in many productions with the American Indian Theatre Company and in a touring one-man show, "Coyote Chews His Own Tale". He consolidated his standing in films with a searing performance as the fiercely angry Magua in Michael Mann's stirring adaptation of "The Last of the Mohicans" (1992). Studi finally entered the limelight via his gritty yet noble interpretation of the title role of Walter Hill's classically elegant $35 million biopic "Geronimo: An American Legend" (1993). The commercial failure of that project sent him back to more fully clothed character roles in the forgettable Jean-Claude Van Damme vehicle "Street Fighter" (1994) and the high profile crime film "Heat" (1995). The latter project reunited him with "Last of the Mohicans" writer-director Mann and cast him as a L.A. cop aiding Al Pacino in his pursuit of professional thief Robert De Niro and his gang. Studi's distinctive bass voice can often be heard on TV documentaries about the Native American experience. He has also appeared in several historical TV-movies, series and miniseries.