Crabbe was born to Edward Clinton Simmons Crabbe, a real estate broker, and Lucy Agnes (née McNamara) Crabbe, in Oakland, California. He had a brother, Edward Clinton Simmons Crabbe Jr. (1909–1972).

Raised in Hawaii, Crabbe graduated from the Punahou School in Honolulu. He competed in two Olympic Games as a Swimmer. At the 1928 Summer Olympics in Amsterdam, he won the bronze medal for the 1,500 meters freestyle, and at the 1932 Summer Olympics in Los Angeles, he won the gold medal for the 400 meters freestyle when he beat Jean Taris of France by a tenth of a second. He attended the University of Southern California, where he was the school's first All-American Swimmer (1931) and a 1931 NCAA freestyle titlist. He also became a member of the Sigma Chi Fraternity before graduating from USC in 1931.

In 1933, he married Adah Virginia Held (1912 – 2004) and gave himself one year to make it as an actor. If he didn't, he would start law school at USC. Crabbe and his wife were the parents of two daughters, Sande and Susan, and a son, Cullen. Sande died of apparent anorexia in 1957, after a long fast when she was 20; at the time of her death she weighed 60 pounds. He was the maternal grandfather of the college football coach Nick Holt.

In 1936 he was picked over several stars to play Flash Gordon in the very successful Flash Gordon serial, followed by two sequels, released by Universal in 1938 and 1940. The series was shown later extensively on American television in the 1950s and 1960s, then edited for release on home video. He also starred as Buck Rogers for Universal playing the role with dark hair unlike Flash Gordon's blonde hair. In 1939, Crabbe reunited with Betty Grable for a lead role in the mainstream comedy Million Dollar Legs.

Crabbe starred at the Billy Rose's Aquacade at the New York World's Fair in its second year of 1940, replacing fellow Olympic Swimmer and Tarzan actor Johnny Weissmuller.

During World War II Crabbe was contracted to Producers Releasing Corporation in lead roles from 1942-1946 where he portrayed a Western folk-hero version of Billy the Kid in 13 films and 23 as Billy Carson with his sidekick played by actor Al St. John. As a 34 year old married man, Crabbe had a deferment from the draft but made Army training films for the field artillery at Ft. Sill, Oklahoma along with Fuzzy St. John. Crabbe also played some jungle roles for the studio.

Following the war Crabbe appeared opposite Weissmuller as a rival in two jungle films, Swamp Fire (1946) and Captive Girl (1950). Crabbe returned to the jungle for his final serial playing the role of Thun'da in King of the Congo (1952).

In the 1950s, two comic book series were published named after him. Eastern Color published 12 issues of Buster Crabbe Comics from 1951 to 1953, followed by Lev Gleason's The Amazing Adventures of Buster Crabbe for four issues in 1954.

Crabbe was featured frequently in archival footage in the children's television program, The Gabby Hayes Show. Prior to his playing "Captain Michael Gallant" Crabbe had hosted a local NYC based children's film wraparound television series The Buster Crabbe Show. The series, which was set against the backdrop of a ranch foreman's bunk house featured Crabbe engaging his viewers in games, stories, craftmaking, hobbies, informational segments, and interviews with guest performers and personalities in between reruns of old movie serials, westerns and comedies. The Buster Crabbe Show was seen weekday evenings on WOR-TV (Channel 9) in New York City from Monday March 12, 1951, to Friday October 3, 1952. The series returned to the NYC airways on WJZ-TV (Channel 7) (now WABC) on Monday September 21, 1953, and was retitled Buster's Buddies!. The WJZ TV version of the series included a studio audience of kids and became more of a kids' variety show. Despite the addition of the studio audience and Crabbe's personality, Buster's Buddies! was not a hit and it was canceled on Friday March 26, 1954.

Crabbe starred in the television series, Captain Gallant of the Foreign Legion (1955 to 1957) as Captain Michael Gallant; the adventure series aired on NBC. His real-life son, Cullen Crabbe, appeared in this show as the character "Cuffy Sanders".

In 1965, he was inducted into the International Swimming Hall of Fame. During his senior swimming career Crabbe set 16 world and 35 national records. He continued swimming through his sixties, and in 1971 set a world record in his age group. In 1975, marketing guru Jeffrey Feinman, got him a five-book deal with Playboy Press. His first book "Energistics" was an exercise program for seniors. It sold quite well and went into several printings. Feinman then did a series of infomercials with Crabbe that sold a huge amount of diverse products.

Crabbe made regular television appearances, including one on an episode of the 1979 series Buck Rogers in the 25th Century, in which he played a retired fighter pilot named "Brigadier Gordon" in honor of Flash Gordon. When Rogers (Gil Gerard) praises his flying, Gordon replies "I've been doing that sort of thing since before you were born." Rogers (who was born over 500 years earlier) responds "You think so, old timer?" to which Gordon replies "Young man, I know so." In fact, Crabbe had been playing "Buck Rogers" since long before Gerard was born.

He died on April 23, 1983 of a heart attack at age 75 in his Scottsdale, Arizona, home. He is interred at Green Acres Memorial Park in Scottsdale.

During this period of his life, Buster joined the swimming pool company Cascade Industries of Talmadge Road, Edison, New Jersey. In his capacity as Vice President of Sales, promoter and spokesman for Cascade – the world's first "package pool" company – he attended shopping mall openings and fairgrounds combining promotion of his swim camps and Cascade vinyl liner in-ground swimming pools. A pool line was named after him, and pools were sold by "Buster Crabbe Dealers" throughout the eastern seaboard and southern states from 1952 until 1990.