Locke won a nationwide talent search in 1967 for the part of Mick Kelly in a big-screen adaptation of Carson McCullers' novel The Heart Is a Lonely Hunter opposite Alan Arkin. Prior thereto, she had starred in some half-dozen theater productions with husband Gordon Anderson for Circle Players Inc. The Heart Is a Lonely Hunter was released in the summer of 1968 to critical acclaim, garnering Locke an Academy Award nomination as well as two Golden Globe Award nominations for Best Supporting Actress and Most Promising Newcomer. 　　Her next film role was as Melisse in Cover Me Babe, originally titled Run Shadow Run, opposite Robert Forster. In 1971, she co-starred with Bruce Davison and Ernest Borgnine in the psychological thriller Willard, which became a box office hit. Locke made television guest appearances in several drama series throughout the early 1970s, including The F.B.I., Cannon, Barnaby Jones and Kung Fu. In the 1972 Night Gallery episode "A Feast of Blood", she played the victim of a curse planted by Norman Lloyd; the recipient of a brooch that devoured her. Lloyd acted with her again in Gondola, a three-character teleplay with Bo Hopkins, and remarked that Locke gave "a beautiful performance – perhaps her best ever." She was also featured in William A. Fraker's A Reflection of Fear (1972) and had the title role in The Second Coming of Suzanne (1974). 　　Locke's career reached a turning point in 1975 when she took a supporting role in The Outlaw Josey Wales as the romantic interest of Clint Eastwood's eponymous character. This was followed by a lead role alongside Eastwood in the hit action film The Gauntlet (1977). Over the course of their personal relationship, Locke did not work in any capacity on any theatrical motion picture other than with him except for 1977's western The Shadow of Chikara. In 1978, she and Eastwood appeared with an orangutan named Manis in that year's second highest-grossing film, Every Which Way But Loose, an adventure-comedy in which Locke portrayed country singer Lynn Halsey-Taylor. The 1980 sequel, Any Which Way You Can, was equally successful. She recorded several songs for the films' soundtracks and has also performed live in concert with Eddie Rabbitt and Tom Jones. 　　Locke starred as a bitter heiress who joins a traveling Wild West show in Bronco Billy (1980), her only film with Eastwood not to become a major commercial success. She cites Bronco Billy and The Outlaw Josey Wales as her favorites of the movies they made together. The pair's final collaboration as performers was Sudden Impact (1983), the highest-grossing film in the Dirty Harry franchise, in which Locke played a vengeful artist who systematically murders the men who had gang-raped her and her sister a decade earlier. 　　In 1986, Locke made her feature directorial debut with Ratboy, a fable about a boy who is half-rat, produced by Eastwood's company Malpaso. Ratboy only had a limited release in the United States, where it was a critical and financial flop, but was well received in Europe, with French newspaper Le Parisien calling it the highlight of the Deauville Film Festival. Concentrating almost exclusively on directing from that point onward, Locke's second foray behind the camera was Impulse (1990), a thriller starring Theresa Russell as a police officer who goes undercover as a prostitute. Later, she directed the made-for-television film Death in Small Doses (1995), based on a true story, and the independent film Do Me a Favor (1997) starring Rosanna Arquette. 　　After 13 years away from acting, Locke returned to the screen in 1999 with small roles in the straight-to-cable films The Prophet's Game with Dennis Hopper and Clean and Narrow with Wings Hauser. In 2014, the media announced that Locke would serve as an executive producer on the Eli Roth film Knock Knock starring Keanu Reeves.