While working at an advertising agency, he started writing his first novel, Retreat from Oblivion. After it was published by Dutton in 1939, Goodis moved to New York City, where he wrote under several pseudonyms for pulp magazines, including Battle Birds, Daredevil Aces, Dime Mystery, Horror Stories, Terror Tales, and Western Tales, sometimes churning out 10,000 words a day. Over a five-and-a-half-year period, according to some sources, he produced five million words for the pulp magazines.

During the 1940s, Goodis scripted for radio adventure serials, including Hop Harrigan, House of Mystery, and Superman. Novels he wrote during the early 1940s were rejected by publishers, but in 1942 he spent some time in Hollywood as one of the screenwriters on Universal's Destination Unknown. His big break came in 1946 when his novel Dark Passage was serialized in The Saturday Evening Post, published by Julian Messner, and filmed for Warner Bros., with Humphrey Bogart and Lauren Bacall heading the cast. Delmer Daves directed what is now regarded as a classic film noir, and a first edition of the 1946 hardcover is valued at more than $800.

Arriving in Hollywood, Goodis signed a six-year contract with Warner Bros., where he scripted The Unfaithful, a remake of Somerset Maugham's The Letter. Some of his scripts were never produced, including Of Missing Persons and an adaptation of Raymond Chandler's The Lady in the Lake.

Until recently, it was generally believed that Goodis never married. His friend Harold "Dutch" Silver said Goodis never spoke of a wife, and no wife was mentioned in Goodis's obituary. Attorney correspondence also repeatedly stated that Goodis never married.

However, research by Larry Withers and Louis Boxer has produced a marriage license for Goodis and Elaine Astor. It shows that they were married on October 7, 1943 by Rabbi Jacob Samuel Robins, Ph.D., at Ohev Shalom Congregation, 525 South Fairfax Avenue, Los Angeles. According to a divorce decree found in the attic of Philadelphia's City Hall, Astor received a divorce on January 18, 1946.

Withers is Astor's son by a later marriage. He learned about her marriage to Goodis only after her death in 1986 from a stroke.

In 1950, Goodis returned to Philadelphia where he lived with his parents and his schizophrenic brother Herbert. At night, he prowled the underside of Philadelphia, hanging out in nightclubs and seedy bars, a milieu he depicted in his fiction. Cassidy's Girl (1951) sold over a million copies, and he continued to write for paperback publishers, notably Gold Medal. There was a renewed interest in his novels when François Truffaut filmed Down There (1956) as the acclaimed Shoot the Piano Player (1960).

Goodis died at 11:30 p.m. on January 7, 1967, at Albert Einstein Medical Center, Northern Division, not far from his home. He was 49. His death certificate lists "cerebral vascular accident," meaning a stroke, as the cause of death. Days earlier, Goodis had been beaten while resisting a robbery. Some have attributed his death to his injuries. It is also said that he keeled over while shoveling snow. He was buried in Roosevelt Memorial Park, in Pennsylvania.

In 1963, ABC television began airing the television show The Fugitive, the story of Richard Kimble, a doctor who had been wrongfully convicted of murdering his wife. Kimble subsequently escaped and began a long search for the "one-armed man," the person he believed to be the real killer.

Goodis stated that The Fugitive was based on his novel Dark Passage. In 1965, he sued United Artists-TV and ABC for $500,000, alleging copyright infringement. His cousin's law firm, Goodis, Greenfield, Narin and Mann, represented him and several groups supported him, including the Author's League of America, the Dramatist's Guild, and the American Book Publishers Association. Coudert Brothers represented United Artists and ABC.

During a deposition on December 9, 1966, Goodis stated that the Saturday Evening Post had serialized Dark Passage, a fact that would become critical to the case.

One month later, Goodis was dead. The lawsuit continued to wind its way through the courts, however.

The dispute did not so much concern whether the theme of Dark Passage had been used, but whether the book was in the public domain. In a victory for UA and ABC, the District Court held that Goodis had, in effect, "donated his work to the public domain" when he published it in the Saturday Evening Post without using a copyright notice that listed his name.

The Goodis estate appealed. In 1970, the United States Court of Appeals for the Second Circuit reversed the lower court's decision and remanded the case for trial. The decision is reported at Goodis v. United Artists Television, Inc., 425 F.2d 397 (2nd Cir. 1970). The court wrote, "We unanimously conclude that where a magazine has purchased the right of first publication under circumstances which show that the author has no intention to donate his work to the public, copyright notice in the magazine's name is sufficient to obtain a valid copyright on behalf of the beneficial owner, the author or proprietor." (425 F.2d 398-399)

By then, Goodis's main beneficiary, his brother Herbert, was also dead. So in 1972, the Goodis estate agreed that the case now had only "nuisance value" and accepted $12,000 to settle the matter. Despite the significant difference between the initial claim and the final monetary settlement, the case is still regarded as a landmark decision in intellectual property rights and copyright law.

After his death, his work went out of print in the United States, but he remained a popular favorite in France. In 1987, Black Lizard began to reissue Goodis titles. In 2007, Hard Case Crime published a new edition of The Wounded and the Slain for the first time in more than 50 years. Also in 2007 Street of No Return and Nightfall were re-published by Millipede Press.

Goodis has influenced contemporary crime fiction writers, notably Duane Swierczynski, and Ken Bruen. A character in Jean-Luc Godard's 1966 film Made in U.S.A. was named after Goodis.