Graham Greene is an Oneida born in Ohsweken, on the Six Nations Reserve in Ontario. His first brushes with the entertainment industry came when he was an audio technician for rock bands based in Newfoundland and Labrador, when he went by the alias Mabes. He graduated from The Centre for Indigenous Theatre's Native Theatre School program in 1974, which was based in Toronto.

His TV debut was in an episode of "The Great Detective" in 1979, and his screen debut was in 1983 in "Running Brave." He appeared in such films as "Revolution" and "Powwow Highway," as well as the First Nations, CBC TV series "Spirit Bay."

It was his Academy Award-nominated role as Kicking Bird (Lakota: Ziŋtká Nagwáka) in the 1990 film "Dances with Wolves" that brought him fame. He followed this role with films and performances on TV series, including "Thunderheart," "Benefit of the Doubt," "Maverick," "Northern Exposure" and "The Red Green Show." Greene also acted alongside Bruce Willis and Samuel L. Jackson in the 1995 film "Die Hard with a Vengeance," where he played Detective Joe-Rob Lambert. He hosted the reality crime documentary show "Exhibit A: Secrets of Forensic Science."

He co-starred as Slick Nakai with Adam Beach and Wes Studi in the film "A Thief of Time" and "Coyote Waits," both adapted from Tony Hillerman novels of the same names and produced by Robert Redford. In 1992, Greene played the role of Ishi, the last Yahi, in the HBO drama "The Last of His Tribe." He also appeared that year in the contemporary action-mystery film, "Thunderheart" playing Walter Crow Horse, a gruff, savvy local cop living on an Indian reservation. Greene was then featured as Arlen Bitterbuck, a Native American on death row in the Oscar-nominated "The Green Mile."

In 2006, Greene presented the documentary series "The War that Made America," about the Seven Years' War (French and Indian War) of the mid–18th century in North America. In 2007, he appeared as Shylock in the Stratford Shakespeare Festival production of "The Merchant of Venice" as well as "Breakfast with Scot," the first gay-themed film ever to receive this type of approval from a professional sports league (NHL).

He appeared in "The Twilight Saga: New Moon" as Harry Clearwater, Charlie Swan's old friend. He is now working in the science fiction series "Defiance" as Rafe McCawley.