The artwork featured a considerable number of a 1950s and 1960s American comics artists such as Carmine Infantino, Murphy Anderson, Gil Kane, Alex Toth, Bernard Sachs, Frank Frazetta, and Virgil Finlay.

Directly appealing to American public taste for science fiction in the early 1950s, Mystery in Space was launched by DC Comics with adverts in most of their titles published in early 1951 - proclaiming "The Universe Is The Limit In Every Issue Of Mystery In Space" and "The Magazine That Unlocks The Secrets Of The Future" around a copy of the first cover.

[3] It published the Adam Strange series (issues #53–100, #102),[4] and also featured a number of other characters in series of varying length: Mystery in Space #1 featured "9 Worlds To Conquer", the first 10-page tale of the Knights of the Galaxy by Robert Kanigher (under the name Anthony Dion) with art by Carmine Infantino, together with three eight or ten-page non-series science fiction stories by Gardner Fox and John Broome, the first of a series of single page information pieces "Stars and their legends" and a two-page text article "What do you know about comets?

The Adam Strange space opera tales were crafted by Gardner Fox in the Flash Gordon tradition, with the hero caught between two planets and a love a galaxy away, giant menacing robots, dust devils, perils on two worlds, and distinctive art by Carmine Infantino and Murphy Anderson who drew almost all issues until #92 (June 1964).

(Mystery in Space #75, May 1962), which won comic fandoms Alley Award for the "Best Book-Length Story" of 1962, and was fairly unusual for the time inasmuch as it featured a cross-over with other major DC characters, the Justice League of America.

The following year Mystery in Space gained a further Alley Award, for "Comic Displaying Best Interior Color Work" - a result of the stylistic Infantino/Anderson Adam Strange pages.

For this short series, editor Julius Schwartz replaced Joe Kubert with Murphy Anderson as artist, and utilised an unusual format for the day - the Adam Strange story "The Super-Brain of Adam Strange" in issue #87 led straight into the Hawkman story "The Amazing Thefts of the I.Q.

Although the characters returned to solo stories in the following two issues, "Planets in Peril" (Mystery in Space #90, March 1964) was an epic cross-world book-length team-up between Hawkman and Adam Strange.

The cover to #90, with an iconic Adam Strange soaring between Earth and his adopted home, Rann, is often cited as one of the classic science fiction covers of the early 1960s, and this issue was also to have significant impact on DC story continuity in later years as the story first established the links between Rann and Hawkman's world, Thanagar.

The war between the two planets has been the defining subject of many of both Hawkman's and Adam Strange's stories and mini-series in the 1990s and 2000s as well as a theme running right across many DC titles.

In September 2004, DC Comics released DC Comics Presents: Mystery in Space #1, featuring the stories "Crisis on 2 Worlds" written by Elliot S. Maggin with art by J. H. Williams III, and "Two Worlds" by Grant Morrison with art by Jerry Ordway and Mark McKenna.

[9] DC revived Mystery in Space between November 2006 and August 2007 as an eight issue limited series written by Jim Starlin and drawn by Shane Davis.

In 2012 an over-sized Mystery in Space one-shot anthology was published, featuring stories and artwork by Mike Allred, Paul Pope, Nnedi Okorafor, Michael Kaluta, Robert Rodi, Sebastian Fiumara, Ann Nocenti, Fred Harper, Andy Diggle, Davide Gianfelice, Steve Orlando, Francesco Trifogli, Ming Doyle, and Kevin McCarthy.