Bickford had intended to attend the Massachusetts Institute of Technology (MIT) to earn an engineering degree, but while wandering around the country, he became friends with the manager of a burlesque show, who convinced Bickford to take a role in the show. He debuted in Oakland, California, in 1911. Bickford enjoyed himself so much that he abandoned his plans to attend MIT. He made his legitimate stage debut with the John Craig Stock Company at the Castle Square Theatre in Boston in 1912. He eventually joined a road company and traveled throughout the United States for more than a decade, appearing in various productions. In 1925, while working in a Broadway play called Outside Looking In, co-star James Cagney (in his first Broadway role) and he received rave reviews. He was offered a role in Herbert Brenon’s 1926 film of Beau Geste, but anxious not to give up his newfound Broadway stardom, turned it down, a decision he later came to regret. Following his appearance in the critically praised but unsuccessful Maxwell Anderson-Harold Hickerson drama about the Sacco and Vanzetti case, Gods of the Lightning (Bickford was the Sacco character), Bickford was contacted by filmmaker Cecil B. DeMille and offered a contract with Metro-Goldwyn-Mayer (MGM) studios to star in DeMille’s first talking picture, Dynamite. He soon began working with MGM studio head Louis B. Mayer on a number of projects.

Bickford married Beatrice Ursula Allen in 1916, in Manhattan. The couple had a son, Rex, and a daughter, Doris. Some sources have stated that Rex died in 1960, but this is disputed by a newspaper story printed at the time of his father’s death, which said he was aged 42 and married.

Bickford became a star after playing Greta Garbo’s lover in Anna Christie (1930), but never developed into a leading man. Always of independent mind, exceptionally strong-willed, and quick with his fists, Bickford frequently argued and nearly came to blows with Mayer and any number of other MGM authority figures during the course of this contract with the studio. During the production of DeMille’s Dynamite, he punched out his director following a string of heated arguments, primarily related to the interpretation of his character’s role. Throughout his early career on both the stage and later films, Bickford rejected numerous scripts and made no secret of his disdain for much of the material he was offered. Not surprisingly, his association with MGM was short-lived, with Bickford asking for and quickly receiving a release from his contract. He soon found himself blacklisted at other studios, though, forcing him to take the highly unusual step (for that era) of becoming an independent actor for several years. His career took another turn in 1935, when he was mauled by a lion and nearly killed while filming East of Java. While he recovered, he lost his contract with Fox and his leading-man status owing to extensive neck scarring suffered in the attack, coupled with his advancing age. Soon, he made a very successful transition to character roles, which he felt offered much greater diversity and allowed him to showcase his talent to better effect. Much preferring the character roles that now became his forte, Bickford appeared in many notable films, including The Farmer’s Daughter, Johnny Belinda, A Star is Born, and Not As a Stranger.

On April 16, 1958, Bickford appeared with Roger Smith in “The Daniel Barrister Story” on NBC’s Wagon Train. In this first-season episode, Daniel Barrister, played by Bickford, objects to medical treatment for his wife, Jenny, the victim of a wagon accident. Meanwhile, Dr. Peter H. Culver, played by Smith, has successfully fought a smallpox epidemic in a nearby town. He is brought to the wagon train by scout Flint McCullough, portrayed by series regular Robert Horton, to treat Mrs. Barrister. Viewers never knew if Barrister yielded to allow Dr. Culver to treat Jenny.

Bickford received two stars on the Hollywood Walk of Fame in 1960. His motion-picture star is located at 6780 Hollywood Boulevard, and his television star is located at 1620 Vine Street.

In 1965, Bickford published his autobiography, Bulls Balls Bicycles & Actors.

The Virginian 1966 – 1967 played Shiloh’s owner as Grainger

Bickford died in Los Angeles on November 9, 1967, at age 76, of pneumonia and a blood infection after being hospitalized for an extended period. Jennifer Jones, who was a close friend of Bickford’s, attempted suicide on the day of his death. Whether her attempt was related is unknown.