Byron was born Imogene Audette Burkhart on December 10, 1925, in Paducah, Kentucky. Her parents were Anna Gertrude (née Bastin; 1906 – 1988) and Edward Burkhart (1892 – 1958). Her family moved to Louisville when she was still quite young, and then to California when she was 19 during World War II. She appeared briefly as a singer on radio, first with Tommy Dorsey's band, followed by a stint with Jan Savitt's group. She then studied drama from 1947 to 1950, followed by a run with the Players Ring, a theatre group that did not pay well, but offered the performers needed exposure. There, in a play titled Merrily We Roll Along, she came to the attention of Harry Sauber, elderly talent adviser for Sam Katzman. She was asked to read from the script and imitate a British accent, which she did. She got her union card then and there. When asked her name, she replied Imogene Burkhart. Katzman rejected that name, so she volunteered the stage name, Jean Byron, which she had already been using and which the Columbia Pictures brass found more palatable.

In the 1950s, Byron appeared in several B-movies, including The Magnetic Monster and Serpent of the Nile, in addition to guest roles on The Millionaire, The Pepsi-Cola Playhouse, Science Fiction Theatre, Fury, and Bourbon Street Beat. Byron also served as spokeswoman for Revlon and Lux products on NBC's The Rosemary Clooney Show.

Byron was married to actor Michael Ansara from 1955 to 1956. Some sources have it as 1949 to 1956. The couple had no children and Byron never remarried.

In 1959, Byron landed a semiregular spot on CBS's The Many Loves of Dobie Gillis playing Dr. Imogene Burkhart, her real name. During her time on the show, she was cast in a spinoff pilot about Dobie Gillis' girlfriend, Zelda, where she would have played the girl's mother. However, the pilot was not picked up. In the show's final season, Byron convinced producers to allow her character to discard the plain, repressed appearance she presented, and show a more modern version of a schoolteacher.

The following year, she starred in the short-lived soap opera Full Circle, which also co-starred Dyan Cannon. In 1963, she won the role of Natalie Lane on The Patty Duke Show. After the series ended in 1966, she continued appearing in guest roles on Batman, Marcus Welby, M.D., Maude, and Hotel.

Byron's last on-screen role was in the 1999 television movie The Patty Duke Show: Still Rockin' in Brooklyn Heights.

On February 3, 2006, Byron died in Mobile, Alabama, of complications following hip replacement surgery.