Cardinal was a leader of a youth group petitioning to get the Canadian government to build more schools on Indian reservations in the province of Alberta when she was cast in a small role in a 1971 Canadian docudrama on the life of Albert Lacombe, a 19th century Roman Catholic missionary. Though uncomfortable with having to portray Lacombe as a savior, Cardinal made the most of her part and, bitten with the acting bug, began performing in films, TV, on stage, and even in industrial films. By 1986, when she moved to the US to pursue a career in Hollywood, she was nationally known in Canada. Strong parts in feature films followed. Having auditioned for Kevin Costner by translating the dialogue into her native Cree, she landed the role of Black Shawl, the knowing wife of medicine man Kicking Bird in "Dances With Wolves". In 1991, she was cast by director Bruce Beresford in "Black Robe", which earned her critical acclaim for her death scene, complete with an arrow in her neck. Cardinal went on to portray Bangor, the companion to Vermont logger Rip Torn in "Where the Rivers Flow North", making a strong impression in a scene in which she laments not having children, and in Sam Shepard's "Silent Tongue" (1993), she had the title role as the ghost of a raped and murdered woman who haunts her husband. As the decade wound to a close, Cardinal portrayed the title character's wise grandmother in "The Education of Little Tree" (1997) and had a featured role in the popular Sundance premiere "Smoke Signals" (1998).

Cardinal has also worked extensively on TV, often in PBS dramas or films on historical First American figures and stories. She broke into network TV with "Gunsmoke: Return to Dodge" (CBS, 1987), and followed with the PBS "Wonderworks" special "Places Not Our Own" (billed as Tantoo Martin-Cardinal), as one of the metis women trying to cope with the difficulties of the Depression. Cardinal also appeared in "Tecumseh: The Last Warrior" (TNT, 1995) and was featured in "Grand Avenue" (HBO, 1996). She made the first of her recurring appearances on the CBS drama series "Dr. Quinn, Medicine Woman" in 1993, cast as Snow Bird, the stalwart Cheyenne friend of frontier physician Jane Seymour. More recently, Cardinal played a relative of twin sisters separated at birth and reunited as adults in the heartwarming "Hallmark Hall of Fame" production "The Lost Child" (CBS, 2000).