Writer-editor Stan Lee described Thor's genesis as following the creation of the Hulk: "I thought it would be fun to invent someone as powerful as, or perhaps even more powerful than, the Incredible Hulk. But how do you make someone stronger than the strongest human and nearly as strong as Superman? It finally came to me: Don't make him human — make him a god. Since DC had all powerful Superman I decided to create someone nearly on his level for Marvel."

Following Thor's debut in the science fiction/fantasy anthology title Journey into Mystery, the 13-page feature "The Mighty Thor" continued to be plotted by Lee but scripted by Lee's brother Larry Lieber or Robert Bernstein (working under the pseudonym "R. Berns"). Penciling was by either Jack Kirby, Joe Sinnott, Don Heck, or, for a single issue, Al Hartley. Then with Journey into Mystery #101 (Feb. 1964), the series began a long and definitive run by Lee and Kirby that lasted until the by-then-retitled The Mighty Thor #179 (Aug. 1970).

The five-page featurette "Tales of Asgard" was added in Journey into Mystery # 97 (Oct. 1963) followed by "The Mighty Thor" becoming the dominant cover logo with issue #104 (May 1964). The feature itself expanded to 18 pages in #105, which eliminated the remaining anthological story from each issue; it was reduced to 16 pages five issues later.

Journey into Mystery was retitled The Mighty Thor with issue #126 (March 1966). "Tales of Asgard" was replaced by a five-page featurette starring the "The Inhumans", from #146–152 (Nov. 1967 – May 1968), after which featurettes were dropped and the Thor stories reverted to Marvel's then-standard 20-page length.

Once Kirby left the book, John Buscema and Neal Adams each drew a few issues. Buscema became the regular artist with issue #182 (Nov. 1970) and continued to draw the book almost without interruption until #278 (Dec. 1978).

Lee stopped scripting soon after Kirby left, and during Buscema's long stint on the book, the stories were mostly written by Gerry Conway, Len Wein or Roy Thomas. Thomas continued to write the book after Buscema's departure, working much of the time with the artist Keith Pollard, but for several years The Mighty Thor had a changing creative team.