Wrightson illustrated adaptions of works by well-known horror writers, including "The Black Cat" by Edgar Allan Poe and "Cool Air" by H. P. Lovecraft.

[4] He received training in art from watching Jon Gnagy on television, reading comics, particularly those of EC, as well as through a correspondence course from the Famous Artists School.

[9] He continued to work on a variety of mystery and anthology titles for both DC and, a few years later, its principal rival, Marvel Comics.

It was for Marvel's Chamber of Darkness and Tower of Shadows titles where he was first encouraged to slightly simplify his intricate pen-and-ink drawing, and where his lush brushwork, a hallmark of his comics inking in the 1970s, was first evidenced.

At one point Wrightson lived in the same Queens apartment building as artists Allen Milgrom, Howard Chaykin and Walter Simonson.

'"[11] With writer Len Wein, Wrightson co-created the muck creature Swamp Thing in House of Secrets #92 (July 1971) in a standalone horror story set in the Victorian era.

[13] Abigail Arcane, a major supporting character in the Swamp Thing mythos was introduced by Wrightson and Wein in issue #3 (Feb.-March 1973).

[17] Wrightson had originally been asked by DC to handle the art for its revival of The Shadow, but he left the project early on when he realized he could not produce the necessary minimum number of pages on time, along with his work on Swamp Thing.

As with BadTime Stories, Wrightson experimented with different media in these black-and-white tales: Edgar Allan Poe's "The Black Cat" featured intricate pen-and-ink work which stood in direct contrast with his brush-dominated Swamp Thing panels.

[10] Wrightson spent seven years drawing approximately 50 detailed pen-and-ink illustrations to accompany an edition of Mary Shelley's novel Frankenstein.

[25] The Freakshow graphic novel, written by Bruce Jones and illustrated (via pen, brush, and ink with watercolors) by Wrightson, was published in Spain in 1982 and serialized in Heavy Metal magazine in the early 1980s.

[28] Jim Starlin and Wrightson produced Heroes for Hope, a 1985 one-shot designed to raise money for African famine relief and recovery.

[32][33] Starlin and Wrightson collaborated on two miniseries in 1988, The Weird[34] and Batman: The Cult,[35] as well as Marvel Graphic Novel #29 (featuring the Hulk and the Thing) and Punisher P.O.V.

[39] Wrightson did concept art for film and television, working on productions including The Faculty, Galaxy Quest, Spider-Man, The Mist, Land of the Dead, and Serenity.

[44] Wrightson and his wife announced in January 2017 that he was retiring due to having limited body function after multiple brain surgeries.

[11] "The First Day of the Rest of Your Life", the April 2, 2017, season 7 finale of the TV series The Walking Dead, was dedicated to Wrightson's memory.

[46] Wrightson's death met with a series of testimonials and tributes by colleagues and professional admirers that included Joss Whedon, Neil Gaiman, Guillermo del Toro, Walter Simonson, and Mike Mignola.

Regarding the famously reproduced two-page spread from that work depicting Frankenstein's laboratory, Simonson said of that image, "It's so complicated and yet he's able to show you what he wants you to see.

Comics analyst and historian Scott McCloud called that image a "riot of detail", saying, "It might take a moment before you even notice the corpse laying at the bottom of the composition on the left.

'"[11] During a 2016 tour of his extensive library of art and pop culture memorabilia, Del Toro named Wrightson's Frankenstein as the work whose original artwork was the hardest to find, saying, "They are very rare.