He received training in art from reading comics, especially those produced by EC as well as a correspondence course.
Began working in 1966 for the Baltimore Sun as an illustrator. In 1967, after meeting artist Frank Frazetta in a comic convention in New York he was inspired to produce his own stories. In 1968 he showed copies of his sequential art to DC comics editor Dick Giordano and was given a job.
His first professional comic work appeared in House of Mystery #179 in 1968. He continued to work on a variety of mystery and anthology titles for both DC and their principal rival Marvel Comics. In 1971 he co-created the massive muck creature Swamp Thing with writer Len Wein for DC. The popular character was given his own book and the issues illustrated by Wrightson are acknowledged as some of the most beautifully accomplished comics of all time.
By 1974 he had left DC to work at Warren where he produced a series of original horror work as well as adaptations of stories by H.P. Lovecraft and Edgar Allan Poe. Though he continued to produce sequential art he also began producing artwork for numerous posters, prints, calendars, and even coloring books. He produced the poster for the film "Creep Show" and album covers for a number of bands including Meatloaf. He has also contributed illustrations for writer Stephen King's werewolf story "Cycle of the Werewolf".