After debuting in Strange Tales #110 and returning in the next issue, the nine- to 10-page feature "Doctor Strange" skipped two issues and then returned permanently with #114 (Nov. 1963). Steve Ditko's surrealistic mystical landscapes and increasingly head-trippy visuals helped make the feature a favorite of 1960s college students, according to accounts. Ditko, as co-plotter and later sole plotter, in the "Marvel Method", would eventually take Strange into ever-more-abstract realms that nonetheless remained well-grounded thanks to Stan Lee's reliably humanistic, adventure/soap opera dialog. Doctor Strange shared the "split book" Strange Tales with solo adventures of Fantastic Four member the Human Torch (whose feature had begun in issue #101), and, beginning with #135, with its replacement feature, Nick Fury, Agent of S.H.I.E.L.D.

While Lee and Ditko themselves interacted less and less as each went their different creative ways, Doctor Strange's storyline culminates with what historians consider one of modern comics' great moments: the introduction, in issue #146 (July 1966), of Ditko's grand and enduring conception of Eternity, the personification of the universe, depicted as a majestic silhouette whose outlines are filled with the cosmos. It was a groundbreaking creation at a time long before such cosmic conceits were commonplace, and Ditko's final bow on the feature.

Doctor Strange's first namesake comic book, written by Roy Thomas with art by penciler Gene Colan, lasted only until issue #183 (Nov. 1969), by which point Strange had been given, separately, both a new secret/civilian identity as "Dr. Stephen Sanders" and, previously, making that possible, a full-face cowl in an effort to more resemble a Marvel superhero and help low sales. These changes were unsuccessful and the series was subsequently abandoned. The cancellation was abrupt (there was a "Next Issue" blurb in the last edition), and loose ends were tied up in Sub-Mariner #22 (Feb. 1970) and The Incredible Hulk #126 (April 1970).

Strange's next appearance was a backup solo tale in the showcase title Marvel Feature #1 (Dec. 1971) This story not only tied into the issue's lead feature, the creation of the loosely affiliated antihero team the Defenders, but also led into a new ongoing feature for the sorcerer in Marvel Premiere #3-14 (July 1972 - March 1974). This series continued into a solo book generally titled as Doctor Strange: Master of the Mystic Arts, which ran 81 issues (June 1974 - Feb. 1987). An acclaimed[citation needed] early arc by writer Steve Englehart and penciler/co-plotter Frank Brunner, featured the death of Strange's mentor, the Ancient One, followed by a storyline in which Strange witnessed the Creation, or re-creation, of the universe. Reflecting that era's trend toward "cosmic" characters and stories — a trend ironically begun in the Lee-Ditko '60s stories — this turn away from more traditionally occult, supernatural stories helped propel for 15 years under various teams.