He began playing in bands starting in the sixth grade, generally in the role of lead singer, songwriter and rhythm guitarist, and also wrote music reviews for a number of publications.

[5] He contributed to the company's line of horror comics notably with the creation of the Creature Commandos in Weird War Tales #93 (Nov. 1980)[6] and I…Vampire in House of Mystery #290 (March 1981).

[11] After writing a negative review of the Grateful Dead's 1980 album Go to Heaven which was published in Rolling Stone, DeMatteis ended his career as a music critic.

[12] He saw the series as an opportunity to both delve more into the psychology of the title character than he had been able to in The Defenders and to continue his collaboration with Budiansky from the recently canceled Ghost Rider, later recalling, "We'd get on the phone, start talking, and the stories would come so easily.

[14] DeMatteis and illustrator Jon J. Muth created the graphic novel Moonshadow, for Marvel's Epic line: the groundbreaking story was the first fully painted series in American comics.

[17] When that title was cancelled[18] in the wake of the company-wide crossover Legends, DeMatteis stayed through its relaunch as Justice League International,[19] scripting over the plots of Keith Giffen.

JLI took such lesser-known DC characters as Martian Manhunter, Blue Beetle, Booster Gold, Mister Miracle, Captain Atom, and Power Girl and turned the then-current preoccupation with "grim 'n' gritty" superheroes on its head.

The lighthearted series emphasized the absurd aspects of people with strange powers, wearing colorful costumes, volunteering to fight evildoers.

[5] Back at Marvel, DeMatteis again succeeded Conway, this time as writer of The Spectacular Spider-Man in 1991, taking the series in a grimmer, more psychologically oriented direction.

In collaboration with regular artist Sal Buscema, DeMatteis' story arc "The Child Within" (#178–184) featured the return of the Harry Osborn Green Goblin.

[24] In 1994, DeMatteis took over from David Michelinie as writer of The Amazing Spider-Man #389–406 for a run that included the apparent death of Peter Parker's Aunt May[25] and the beginnings of the "Clone Saga" arc.

The following year, Ploog and DeMatteis announced they were collaborating on a five-issue miniseries, Stardust Kid, from the Image Comics imprint Desperado Publishing.

[citation needed] In June 2010, DeMatteis's children's fantasy novel, Imaginalis, was published by Katherine Tegen Books, an imprint of HarperCollins.

In 2009, he wrote a five-issue comic book limited series, illustrated by Mike Cavallaro, The Life and Times of Savior 28, which was released by IDW Publishing in 2009.

In 2021, Marvel announced a new limited series titled Ben Reilly: Spider-Man written by DeMatteis with art by David Baldeón, released in 2022.

Through a Kickstarter campaign, he presented the DeMultiverse, a collection of four "pilot issues" of comics titled Anyman, Godsend, Layla in the Lands of After and Wisdom.

[41] The second wave of DeMatteis's Spellbound series launched on Kickstarter in the summer of 2024, offering second chapters of all the DeMultiverse titles, with more planned for the future.

DeMatteis has also written for television, having scripted episodes of the 1980s incarnation of The Twilight Zone, the syndicated series The Adventures of Superboy and Earth: Final Conflict, as well as for the animated series The Real Ghostbusters, Justice League Unlimited, Legion of Super Heroes, Batman: The Brave and the Bold, Ben 10: Ultimate Alien, Sym-Bionic Titan, ThunderCats, Teen Titans Go!