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In 1968 Wrightson started to work at the Baltimore Sun as an editorial cartoonist. That same year he attended a New York comicbook convention where he showed some of his artwork around. Soon afterwards he was offered work by DC Comics and quited his job at the Baltimore Sun and moved to New York.

In 1969 his first professional work was published in House of Mystery #179 for DC Comics and in 1970 his first work for Marvel Comics was published in Chamber of Darkness #7.

In 1971 Bernie Wrightson penciled a 8 page story, written by legendary Len Wein, which was published in House of Secrets #92. The story was called Swamp Thing. The response to the Swamp Thing story was so big that it spawned a regular series in 1972. Wrightson on pencils and Len Wein as writer. In 1974 Wrightson left Swamp Thing after issue #10 and started to work for Warren.

From 1976 to 1978 Wrightson along with Barry Windsor-Smith, Jeff Jones and Michael Kaluta were partners in a venture known as The Studio. In 1979 the definitive book about Bernie Wrightson; A Look Back was published for the first time.

In 1983 Bernie Wrightson's Frankenstein written by Mary Shelley was published. The classic story of tragic horror was brought to life with more than 45 full-page black and white illustrations by Wrightson! That same year Wrightson also illustrated the Stephen King story Cycle of the Werewolf.

From 1988-1993 Wrightson penciled several highly acclaimed projects: Batman: The Cult in 1988 for DC Comics, Punisher P.O.V. in 1991 for Marvel Comics and Captain Sternn: Running Out of Time in 1993 for Kitchen Sink Press.

In 1997 Wrightson penciled the Batman/Aliens crossover published by DC Comics and Dark Horse. Also that year Freak Show was reprinted for the first time in black and white. Wrightson created this story together with Bruce Jones and was first published in 1982 in Heavy Metal magazine.