The first 18 issues featured the regular Archie gang in stories that were more surreal than the normal Archie series. Beginning with issue #19, the Archie gang was dropped (although the book was still called Archie's Mad House), and the title began featuring various monsters, space creatures, and other wacky characters in non-continuity short stories. The gags in the comics often parodied the latest fads and popular culture. The main focus was on one-off stories and single-page (sometimes single-panel) gags that featured no continuing characters, although sometimes characters became recurring.
The most noteworthy recurring character began was issue 22 when Sabrina the Teenage Witch was introduced, with art by Archie mainstay Dan DeCarlo. This issue has become one of the most sought after Archie issues of the Silver Age. Sabrina began making intermittent appearances through issue #74, and then transitioned over to other titles, such as Archie's TV Laugh-Out and her own Sabrina title. Other recurring characters included a bungling but victorious superhero named Captain Sprocket and a hippie named Clyde Didit (occasionally spelled Diddit) who served as the book's mascot for a while.
The Madhouse Glads run introduced yet another gang of characters into the Archie universe, which consisted of a youthful rock group who lived in the town of Riverdale and occasionally interacted with the regular Archie character. But much like the gang introduced in That Wilkin Boy, several years earlier, the Madhouse Glads characters never caught on with fans like the Josie gang did. Madhouse then returned to the series' irregular, nonsensical style before finally being discontinued.