He was drafted in 1944 into the United States Army, and saw Service in the Philippines during the last days of World War II.

After the war, Derek had a small role in A Double Life (1947) when he was approached by Humphrey Bogart, who renamed him John Derek and cast him as Nick (Pretty Boy) Romano, an unregenerate killer, in Knock on Any Door (1949), a socially conscious melodrama directed by Nicholas Ray. Derek was recognized as a talented newcomer, "plainly an idol for the girls", as Bosley Crowther put it in a review for The New York Times. The Los Angeles Times called him "a handsome hot-eyed newcomer who makes the case for this product of the city's slums - 'live fast, die young and have a good looking corpse' - all too fascinating for everybody's comfort."

Derek married Turkish-born prima ballerina Pati Behrs Eristoff in 1948.

Derek followed that picture with a supporting role as the son of Broderick Crawford in All the King's Men (1949), the Best Picture Oscar winner for its year, starring Broderick Crawford. In September 1950 the actor had his name formally changed to "John Derek".

They had a son, Russell Andre (1950–1999), who was paralyzed in a 1969 motorcycle accident, and a daughter, Sean Catherine (born 1953), who later wrote a memoir titled Cast of Characters, published in 1982, about their dysfunctional relationship. Derek walked out on his wife and family in August 1955 after meeting 19-year-old aspiring Swiss Actress Ursula Andress, who spoke almost no English when they met. He and Behrs were divorced in 1956.

Instead Columbia put him in another swashbuckler, Mask of the Avenger (1951), then they gave him a good dramatic role in a prestige film, Saturday's Hero (1951), as a college football player. The novel had been bought specifically as a vehicle for Derek. He was in a crime noir, The Family Secret (1951), then reunited with Crawford in Scandal Sheet (1952).

Derek was borrowed by Republic Pictures for a war film, Thunderbirds (1952). He went back to Columbia for Prince of Pirates (1953), a swashbuckler for Sam Katzman; two Westerns, Ambush at Tomahawk Gap (1953), with John Hodiak and The Last Posse (1953) with Crawford. He was back with Hodiak for Mission Over Korea (1953), a Korean War film, then was borrowed by Republic Pictures for Sea of Lost Ships (1953). In July 1953 Derek left Columbia.

In March 1954 Derek signed a long term contract with Paramount.

Derek made several films for Paramount: Run for Cover (1955), a Western with James Cagney and Nicholas Ray and The Leather Saint (1956), a boxing film. He also appeared as Joshua in The Ten Commandments (1956). He wanted to make a film about Joaquin Murrieta but it was never made.

In 1957, after finalizing his divorce from Behrs, he married Andress in a quickie Las Vegas ceremony, but she left him in 1965 for French actor Jean-Paul Belmondo.

Derek appeared alongside his second wife Ursula Andress in Nightmare in the Sun (1965), which Derek co-produced. He turned to directing with a war film, Once Before I Die (1965), also with Andress.

Derek subsequently became involved with American Actress Linda Evans, at the time starring in television's The Big Valley, who reduced her appearances on the show to spend more time with him, and financed his alimony and child support payments to Behrs, as he had quit acting by then to pursue photography and directing. They married in Mexico in 1968, with Sean as a witness.

He directed A Boy... a Girl (1969) with Dean Paul Martin, and Childish Things (1969) with his third wife, Linda Evans.

Derek, Evans and 16-year-old high school dropout Mary Cathleen Collins traveled to the Greek island of Mykonos in 1973 to make the film And Once Upon a Time (unreleased until 1981, under the title Fantasies). During filming, Derek and Collins began an affair. Evans returned to the United States and filed for divorce in 1974, but Derek and Collins stayed in Europe until she turned 18 in November of that year, in order that he would avoid statutory rape charges.

Collins became known to the public as Bo Derek following their marriage on June 10, 1976 in Las Vegas, and achieved international fame in 1979 with her role in the Blake Edwards film 10. The couple remained together until John died in 1998.

They intended to follow it with Eve and That Damned Apple but when Universal delayed financing they decided to make Bolero (1984) for Cannon, which was an unhappy experience for the Dereks. His last film as Director was Ghosts Can't Do It (1990).

John Derek died on May 22, 1998, from cardiovascular disease in Santa Maria, California at the age of 71. His remains were cremated.