Westlake wrote constantly in his teens, and after 200 rejections, his first short story sale was in 1954. Sporadic short story sales followed over the next few years, while Westlake attended Champlain College of Plattsburgh, New York (now defunct) and Binghamton University in Binghamton, New York. He also spent two years in the United States Air Force.

Westlake moved to New York City in 1959, initially to work for a literary agency while writing on the side. By 1960, he was writing full-time. His first novel under his own name, The Mercenaries, was published in 1960; over the next 48 years, Westlake published a variety of novels and short stories under his own name and a number of pseudonyms.

Jean-Luc Godard's Made in U.S.A. in 1966 was an extremely loose adaptation of The Jugger. Neither the film's Producer nor Godard purchased the rights to the novel, so Westlake successfully sued to prevent the film's commercial distribution in the United States.

Several of Westlake's novels have been made into motion pictures: 1967's Point Blank (based on The Hunter) with Lee Marvin as Parker (changed to Walker); Mise à sac (fr) (based on The Score) with Michel Constantin as Parker (changed to Georges), also in 1967; 1968's The Split (from the book The Seventh) with Jim Brown as Parker (changed to McClain); The Hot Rock in 1972 with Robert Redford; Cops and Robbers in 1973; The Outfit with Robert Duvall as Parker (changed to Macklin), also in 1973; Bank Shot in 1974 with George C. Scott; The Busy Body (with an "all-star cast") in 1967; Slayground with Peter Coyote as Parker (changed to Stone) in 1983; Why Me? with Christopher Lambert, Christopher Lloyd, and J. T. Walsh in 1990; Payback in 1999, the second film made from The Hunter, with Mel Gibson as Parker (changed to Porter); What's the Worst That Could Happen? in 2001 with Martin Lawrence as Dortmunder (changed to Kevin Caffery); Constantin Costa-Gavras adapted The Ax for the European screen in 2005, to great critical and public acclaim – entitled Le Couperet, the film takes place in France and Belgium rather than the novel's setting of New England; Parker in 2013, based on Flashfire, with Jason Statham as Parker.

He was a three-time Edgar Award winner, and alongside Joe Gores and william L. DeAndrea was one of few Writers to win Edgars in three different categories (1968, Best Novel, God Save the Mark; 1990, Best Short Story, "Too Many Crooks"; 1991, Best Motion Picture Screenplay, The Grifters). In 1993, the Mystery Writers of America named Westlake a Grand Master, the highest honor bestowed by the society.

The novel Jimmy the Kid has been adapted three times: in Italy as Come ti rapisco il pupo (it) in 1976; in the U.S. as Jimmy the Kid in 1982 starring Gary Coleman; and in Germany as Jimmy the Kid in 1998 starring Herbert Knaup.

Westlake co-wrote the story for the pilot of the ill-fated 1979 TV series Supertrain with teleplay Writer Earl W. Wallace; Westlake and Wallace shared "created by" credit.

The novel Two Much! has been adapted twice: in France as Le Jumeau (The Twin) in 1984; and in the U.S. as Two Much in 1995 starring Antonio Banderas and Melanie Griffith.

In 1987 Westlake wrote the teleplay Fatal Confession, a pilot for the TV series Father Dowling Mysteries based on the novels by Ralph McInerny. He also appeared in a small role (as the mystery Writer Rich Vincent) in the third-season episode, "The Hardboiled Mystery."

Westlake was himself a Screenwriter. His script for the 1990 film The Grifters, adapted from the novel by Jim Thompson, was nominated for an Academy Award. (Westlake the Screenwriter adapted Jim Thompson's work in a straightforward manner, but Westlake the humourist played on Thompson's name later that year in the Dortmunder novel Drowned Hopes by featuring a character named "Tom Jimson" who is a Criminal psychopath.) Westlake also wrote the screenplay The Stepfather (from a story by Westlake, Brian Garfield and Carolyn Lefcourt), the film of which was sufficiently popular to receive two sequels and a remake, projects in which Westlake was not involved.

While the seventeenth James Bond film GoldenEye was in post-production, Westlake wrote story treatments for the eighteenth James Bond film (eventually titled Tomorrow Never Dies) in collaboration with Bond series writer-producer Michael G. Wilson. None of Westlake's ideas made it into the completed film, but in 1998 the author used the first treatment as the basis for a novel, Fall of the City. The existence of the novel (and its connection to the Bond treatments) was revealed in an article published in issue #32 of the magazine MI6 Confidential; the article also provides a detailed analysis of the two treatments. Fall of the City was published under the title Forever and a Death in June 2017 by Hard Case Crime.

Westlake died of a heart attack on December 31, 2008, while on the way to a New Year's Eve dinner, while he and his wife were on vacation in Mexico.