Born William Broderick Crawford in Philadelphia, Pennsylvania, to Lester Crawford and Helen Broderick, who were both vaudeville performers, as his grandparents had been. His father appeared in films in the 1920s and 1930s; his mother had a minor career in Hollywood comedies, including a memorable appearance as Madge in the classic musical Top Hat. He joined his parents on the stage, working for producer Max Gordon. When vaudeville went into decline, he attended Harvard University for three months, but dropped out to work as a stevedore on the New York docks.

Crawford returned to vaudeville and radio, which included a period with the Marx Brothers on their NBC radio comedy show Flywheel, Shyster, and Flywheel. He played his first serious character as a footballer in She Loves Me Not at the Adelphi Theatre, London in 1932. Crawford's talents were spotted by Noël Coward during the three weeks the play ran. Coward also played in the 1935 Broadway production of 'Point Valaine'.

Early in his career, Crawford was stereotyped as a fast-talking tough guy and frequently played the villain. He gained fame in 1937, when he starred as Lenny in Of Mice and Men on Broadway. He moved to Hollywood, but did not play the role in the film version. (It went to Lon Chaney, Jr..) However, in 1939 Crawford was selected for a supporting role in the production of Beau Geste alongside such major stars as Gary Cooper and Ray Milland. Crawford followed this up with another important supporting actor role in the 1942 gangster spoof Larceny, Inc., a comedy with Edward G. Robinson, where Crawford played a dumb but lovable tough guy.

During World War II Crawford enlisted in the United States Army Air Corps. Assigned to the Armed Forces Network, he was sent to Britain in 1944 as a sergeant, serving as an announcer for the Glenn Miller American Band.

In 1949 he reached the pinnacle of his acting career when he was cast as Willie Stark, a character based on Louisiana politician Huey Long, in All the King's Men, a film based on the popular novel of the day by Robert Penn Warren. The film was a huge hit, and Crawford's performance as the blustering Governor Stark won him the Academy Award for Best Actor. The following year he starred in another hit 'A'-list production, Born Yesterday.

Until filming All the King's Men, Crawford's career had been largely limited to 'B' pictures as a supporting or character actor. Crawford was well aware that he did not fit the role of a handsome leading man, once describing himself as looking like a "retired pugilist". He could also be difficult to work with, and was well known for his prodigious drinking on the set. Nevertheless, he had excelled in roles playing the toughest criminal of all, such as 1955's Big House, U.S.A., where Crawford had to convincingly play the role of a convict who leads a band of hardened criminals such as Charles Bronson, Ralph Meeker, and William Talman. Crawford's Academy Award and larger-than-life persona eventually won him more diverse roles, and he would appear in such varied films as Phil Karlson's Scandal Sheet (1952), Fritz Lang's Human Desire (1954), Federico Fellini's Il bidone (1955) and Richard Fleischer's Between Heaven and Hell (1956). He appeared also in Stanley Kramer's Not as a Stranger (1955), "the worst film with the best cast"; and he even tried the Europeansword and sandal films in Vittorio Cotaffavi's La vendetta di Ercole (1960) also known in USA as Goliath and the Dragon.

In 1955 television producer Frederick Ziv of ZIV Television Productions offered Crawford the lead role as "Chief Dan Mathews" in the police drama Highway Patrol, which dramatized law enforcement activities of the California Highway Patrol (CHP). ZIV operated on an extremely low budget of $25,000 per episode of Highway Patrol, with ten percent of gross receipts due to Crawford under his contract. While the show's scripts were largely fictional, the use of realistic dialogue and Crawford's convincing portrayal of a hard-as-nails police chief helped make the show an instant success. Highway Patrol remained popular during its four years (1955–1959) of first-run syndication, and would continue in repeat syndication on local stations across the U.S.A. for many years afterward. For much of the period from 1955 until 1965 most of Crawford's television roles involved ZIV Television, who was among the relative handful of producers willing to accept the occasional challenges inherent in working with the hard-living Crawford. Years later Ziv admitted to an interviewer, "To be honest, Broderick could be a handful!"

Highway Patrol helped revive Crawford's career and cement his 'tough guy' persona, which he used successfully in numerous movie and TV roles for the rest of his life. Fed up with the show's hectic shooting schedule, Crawford quit Highway Patrol at the end of 1959 in order to make a film in Spain and to get his drinking under control.

Crawford's successful run as Chief Dan Mathews in Highway Patrol earned him some two million dollars under his contract with ZIV, who eventually paid him in exchange for Crawford's agreement to sign for the pilot and subsequent production of a new ZIV production, King of Diamonds. Recently back from Europe, and having temporarily stopped drinking, Crawford was signed to play the starring role as diamond industry security chief John King. King of Diamonds was picked up for syndication in 1961, but ran for only one season before being cancelled. In 1962, after the end of King of Diamonds, Crawford returned to acting in motion pictures. Since 1960, he had also begun to accept occasional roles in European-made films. Between 1962 and 1970, Crawford appeared in no less than seventeen additional films, though many of them failed to generate much box office success.

After 1970, Crawford again returned to television. From 1970 to 1971, he played the role of Dr. Peter Goldstone in The Interns. He would eventually make a series of guest appearances on several TV programs, while starring in several made-for-TV movies.

Playing on a stereotype of his famous TV role, he wore the trademark fedora and black suit when he made an appearance as guest host of a 1977 episode of NBC's Saturday Night Live that included a spoof of Highway Patrol, featuring Dan Aykroyd, a longtime fan of the original show, and one in which he portrayed FBI director J. Edgar Hoover, in a humorous send-up of Hoover's suspect sexuality. In an episode of the TV series CHiPs Crawford appeared as himself, recognized after being stopped by Officer Poncherello, who presses a reluctant Crawford to give his trademark line from Highway Patrol ("Twenty-One-Fifty to Headquarters!").

Musician Webb Wilder's instrumental, "Ruff Rider" (on the album It Came From Nashville), is dedicated to Broderick Crawford in admiration of his Highway Patrol character's ability to solve any crime committed in California by setting up a road block. Crawford worked in 140 motion pictures and television series during his career and remained an especially durable presence in television. His last role was as a film producer who is murdered in a 1982 episode of the "Simon and Simon" television series. Ironically, the actor who played the part of the suspected murderer was Stuart Whitman, who had played the recurring part of Sergeant Walters on "Highway Patrol".

Throughout his adult life, Crawford was prone to bouts of heavy alcohol consumption, and was known for eating large meals. These habits contributed to a serious weight gain for Crawford during the 1950s. His weight and penchant for heavy drinking contributed to several injuries suffered on the set of Highway Patrol. It became particularly difficult for Crawford to do certain scenes, such as when he had to enter and exit a police helicopter. In 1958, Crawford broke his ankle while exiting the helicopter and was forced to wear an ankle cast, which may be seen in some episodes.

Crawford's heavy drinking increased during the filming of Highway Patrol, eventually resulting in several arrests and stops for driving under the influence of alcohol (DUI), which eventually gained him a suspended driving license. While representing the California Highway Patrol as "Chief Matthews", Crawford was known with considerable embarrassment by the CHP as "Old 502" due to his habit of driving under the influence of alcohol ("Code 502" was the CHP police radio code for drunken driving). According to the show's creator, Guy Daniels, "We got all the dialogue in by noon, or else we wouldn't get it done at all. He [Crawford] would bribe people to bring him booze on the set." The show used their CHP technical advisor, Officer Frank Runyon, to keep the actor sober: "I was told to keep that son of a bitch away from a bottle. I think his license was suspended. Some scenes had to be shot on private roads so that Brod could drive." Eventually the drinking strained the show's relationship with the CHP and Crawford's relationship with ZIV.

Crawford married three times, and he had two sons (Kelly and Kim) from his marriage to actress Kay Griffith.

He died of a series of strokes in 1986 at the age of 74 in Rancho Mirage, California. He has two stars on the Hollywood Walk of Fame, one for motion pictures at 6901 Hollywood Boulevard and another for television at 6734 Hollywood Boulevard.