In 1954 Garner had a nonspeaking role in the Broadway production of The Caine Mutiny Court Martial. He moved on to television commercials, and then to television roles. His first film role was in The Girl He Left Behind, but in the late 1950s he starred in a popular Western series, Maverick, rotating the starring role with Jack Kelly and Roger Moore. But Garner's popularity eventually made him the sole star of the series. He became a favorite of American fans for this role.
In the 1960s he starred in such films as The Thrill of It All, Move Over, Darling, Boys' Night Out, The Great Escape, The Americanization of Emily, Grand Prix (which gave him a car racing bug) and Support Your Local Sheriff.
In the 1970s he returned to television in another popular role, that of a private investigator in The Rockford Files. In 1986, he received a nomination for the Academy Award for Best Actor for Murphy's Romance.
In 1994, Garner co-starred with Mel Gibson in the movie version of his original Maverick role.