The book, at first titled Adventure Into Mystery, (but renamed three issues later), originally featured monster and science fiction stories and is memorable also for featuring the debut of a prototype of the Hulk in issue #62. With the start of the Silver Age of Comics, Marvel switched the feature to superhero stories and introduced Thor and in issue #83, inspired by the Norse thunder god and by writer Stan Lee's musings that comic books were the mythology of the modern day. Journey into Mystery primarily featured Thor stories through issue #125 and Journey into Mystery Annual #1, at which point the series was retitled The Mighty Thor.

As a consequence of Heroes Reborn, Thor dropped out of his own series beginning with issue #503. The series continued with the "Lost Gods" storyline and then with a rotating cast of characters, until finally ending with Journey into Mystery #521 in 1996.

A second series titled Journey into Mystery was published for nineteen issues, beginning in 1972. This series featured reprints of science fiction and monster tales from the first Journey into Mystery series, as well as Amazing Adult Fantasy, Strange Tales, Strange Worlds, and Tales to Astonish.