He was born in Norfolk, Virginia. During World War I, he served with the Committee of Public Information and the United States Army (1917-1918). Following the war, Leinster became a free-lance writer. In 1921, he married Mary Mandola. They had four daughters. During World War II, he served in the Office of War Information. He won the Liberty Award in 1937 for "A Very Nice Family," the 1956 Hugo Award for Best Novelette for "Exploration Team," a retro-Hugo in 1996 for Best Novelette for "First Contact." Leinster was the Guest of Honor at the 21st Worldcon in 1963. In 1995, the Sidewise Award for Alternate History was established, named after Leinster's story "Sidewise in Time."

Leinster wrote and published over 1,500 short stories and articles over the course of his career. He wrote 14 movie and hundreds of radio scripts and television plays, inspiring several series including "Land of the Giants" and "The Time Tunnel".

Leinster first began appearing in the late 1920s in pulp magazines like Weird Tales and then sold to Astounding Stories in the 1930s on a regular basis. After World War II, when both his name and the pulps had achieved a wider acceptance, he would use either "William Fitzgerald" or "Will F. Jenkins" as names on stories when "Leinster" had already sold a piece to a particular issue. He was very prolific and successful in the fields of western, mystery, horror, and especially science fiction. His novel Miners in the Sky transfers the lawless atmosphere of the Gold Rush, a common theme of Westerns, into an asteroid environment.

He is credited with the invention of parallel universe stories. Four years before Jack Williamson's The Legion of Time came out, Leinster wrote his "Sidewise in Time", which was first published in Astounding in June 1934. This was probably the first time that the strange concept of alternate worlds appeared in modern science-fiction. In a sidewise path of time some cities never happened to be built. Leinster's vision of nature's extraordinary oscillations in time ('sidewise in time') had long-term effect on other authors, e.g., Isaac Asimov's "Living Space", "The Red Queen's Race", or his famous The End of Eternity.

Murray Leinster's 1946 short story "A Logic Named Joe" describes Joe, a "logic", that is to say, a computer. This is one of the first decriptions of a computer in fiction. In this story Leinster was decades ahead of his time in imagining the Internet. He envisioned logics in every home, linked to provide communications, data access, and commerce. In fact, one character said that "logics are civilization."

In 2000, Leinster's heirs sued Paramount Pictures over the film Star Trek: First Contact, claiming that as the owners of the rights to Leinster's short story "First Contact", it infringed their trademark in the term. The U.S. District Court for the Eastern District of Virginia granted Paramount's motion for summary judgment and dismissed the suit (see Estate of William F. Jenkins v. Paramount Pictures Corp., 90 F. Supp. 2d 706 (E.D. Va. 2000) for the full text of the court's ruling). The court found that regardless of whether Leinster's story first coined "first contact", it has since become a generic (and therefore unprotectable) term that described the overall genre of science fiction in which humans first encounter alien species. Even if the title was instead "descriptive" - a category of terms higher than "generic" that may be protectable - there was no evidence that the title had the required association in the public's mind (known as "secondary meaning") such that its use would normally be understood as referring to Leinster's story. The Second Circuit Court of Appeals affirmed the lower court's dismissal without comment.