Highsmith was born Mary Patricia Plangman in Fort Worth, Texas. She was the only child of artists Jay Bernard Plangman (1889-1975), who was of German descent, and Mary Plangman (nee Coates; September 13, 1895 - March 12, 1991). The couple divorced ten days before their daughter's birth. In 1927, Highsmith, her mother and her adoptive stepfather, artist Stanley Highsmith, whom her mother had married in 1924, moved to New York City.

Before her short stories started appearing in print, Highsmith wrote for comic book publishers from 1942 and 1948, while she lived in New York City and Mexico. Answering an ad for "reporter/rewrite," she landed a job working for comic book publisher Ned Pines in a "bullpen" with four artists and three other writers. Initially scripting two comic-book stories a day for $55-a-week paychecks, Highsmith soon realized she could make more money by freelance writing for comics, a situation which enabled her to find time to work on her own short stories and live for a period in Mexico. The comic book scriptwriter job was the only long-term job Highsmith ever held.  From 1942-43, for the Sangor-Pines shop (Better/Cinema/Pines/Standard/Nedor), Highsmith wrote "Sergeant Bill King" stories and contributed to Black Terror and Fighting Yank comics; and wrote profiles such as Catherine the Great, Barney Ross, and Capt. Eddie Rickenbacker for the "Real Life Comics" series. From 1943-1946, under editor Vincent Fago at Timely Comics, she contributed to its U.S.A. Comics wartime series, writing scenarios for comics such as Jap Buster Johnson and The Destroyer. During these same years she wrote for Fawcett Publications, scripting for Fawcett Comics characters "Crisco and Jasper" and others. Highsmith also wrote for Western Comics from 1945 to 1947.  When Highsmith wrote the psychological thriller novel The Talented Mr. Ripley (1955), one of the title character's first victims is a comic-book artist named Reddington: "Tom had a hunch about Reddington. He was a comic-book artist. He probably didn't know whether he was coming or going."

Did Western Comics give her problems when she used the character for her novels?