Garner, the youngest of three children, was born James Scott Bumgarner in Norman, Oklahoma, the son of Mildred and Weldon Warren Bumgarner, a carpet layer. His mother, who was part Cherokee, died when he was four years old. After their mother's death, Garner and his brothers were sent to live with relatives. Garner was reunited with his family in 1934, when Weldon remarried.

Garner grew to hate his stepmother, Wilma, who beat all three boys, especially young James. When he was fourteen, Garner finally had enough of his 'wicked stepmother' and after a particularly heated battle, she left for good. Shortly after the breakup of the marriage, Weldon Bumgarner moved to Los Angeles, while Garner and his brothers remained in Norman. At seventeen, he joined his father in Los Angeles and enrolled at Hollywood High School, where he was voted the most popular student.

In 1954, a friend, Paul Gregory, whom Garner had met while attending Hollywood High School, persuaded Garner to take a non-speaking role in the Broadway production of The Caine Mutiny Court Martial, where he was able to study actor Henry Fonda night after night. Garner subsequently moved to television commercials and eventually to television roles. His first movie appearances were in The Girl He Left Behind and Toward the Unknown in 1956.

He changed his last name from Bumgarner to Garner after the studio had credited him as "James Garner" without permission. He then legally changed it when his first child was born, as he decided she had too many names.

After forty supporting feature film roles, including Sayonara with Marlon Brando, Garner got his big break playing the role of professional gambler Bret Maverick in the comedy Western series Maverick from 1957 to 1960. Maverick eventually made Garner a household name.

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, The Art of Love, and Support Your Local Sheriff!.

Starting with the 1974 season, Garner appeared as private investigator Jim Rockford in The Rockford Files. He appeared for six seasons, for which he received an Emmy Award for Best Actor in 1977. Garner himself ultimately ended the run of the show, despite consistently high ratings, because of the high physical toll on his body.

During the 1980s, Garner played dramatic roles in a number of TV movies, from Heartsounds to Promise and My Name is Bill W..

He was nominated for his first Oscar award for Best Actor in a Leading Role in the movie Murphy's Romance, opposite Sally Field In 2000, after an operation to replace both knees, Garner appeared with Clint Eastwood (who had played a villain in the original Maverick series) in the movie Space Cowboys, also featuring Tommy Lee Jonesand Donald Sutherland. In 2004, Garner starred in the movie version of Nicholas Spark's The Notebook alongside Gena Rowlandsas his wife, directed by Nick Cassavetes, Rowlands' son.

For his contribution to the film and television industry, Garner received a star on the Hollywood Walk of Fame. In 1990, he was inducted into the Western Performers Hall of Fame at the National Cowboy & Western Heritage Museum in Oklahoma City, Oklahoma. In February 2005 he received the Screen Actor's Guild's Lifetime Achievement Award.