With issue #174, EC Comics veteran Joe Orlando was hired by DC to take over as editor of The House of Mystery.

[4] As the Comics Code Authority was now being challenged by both DC and Marvel over content restrictions, the series returned to its overt horror themes.

Artist Bernie Wrightson's first professional comic work was the story "The Man Who Murdered Himself" which appeared in issue #179 (March–April 1969).

[6] Under Orlando's stewardship, the series won a good deal of recognition in the comics industry, including the "Shazam Award for Best Individual Short Story (Dramatic)" in 1972 for "The Demon Within" in issue #201 by John Albano and Jim Aparo, and the "Shazam Award for Best Humor Story" in 1972 for "The Poster Plague" by Steve Skeates and Sergio Aragonés.

[11] Under Berger, the series experimented with long-form storylines in the popular I...Vampire serial created by writer J. M.

A one-shot reprint in color, Welcome Back to the House of Mystery, featured 10 of the most highly regarded stories as selected by Alisa Kwitney in a Cain wraparound by Neil Gaiman and Sergio Aragonés under the Vertigo Comics imprint.

DC's Vertigo imprint began a new ongoing series in May 2008, written by Lilah Sturges and Bill Willingham.

The House of Mystery exists north of Louisville, Kentucky, where it was built and abandoned by Colonel Braitwaithe before the American Civil War,[17] and in the Dreaming.

Batman entered the house in The Brave and the Bold #93, tripped on a floorboard, and would have been shot had his pursuer's gun not jammed.

[18] Superman teamed with Cain against Mxyzptlk, who was attempting to take over the House, in DC Comics Presents #53.

In The New 52's rebooted DC continuity (launched in 2011), the House reappeared in the pages of Justice League Dark, being used as a base for the team.

[20] Two novels were written by Jack Oleck and illustrated by Bernie Wrightson, both published by Warner Books: