Born in Brooklyn, DeMatteis graduated from Midwood High School and Empire State College. He worked as a music critic before getting his start in comic books at DC Comics in the late 1970s. He contributed to the company's line of horror comics. He began writing for Marvel Comics in 1980 on The Defenders, and had a lengthy run on Captain America, paired with penciler Mike Zeck.
In 1987, DeMatteis and Zeck re-teamed for the "Kraven's Last Hunt" arc that ran throughout Marvel's then three Spider-Man titles. DeMatteis and illustrator Jon J. Muth created the graphic novel Moonshadow, the first fully-painted series in American comics for Marvel's Epic line. DeMatteis followed this with A Tale, a hallucinatory vampire story drawn by Kent Williams, and the 1986 Doctor Strange graphic novel Into Shambhala.
Moving back to DC, DeMatteis succeeded Gerry Conway as writer of the superhero-team title Justice League of America. When that series was cancelled in the wake of the company-wide crossover Legends, DeMatteis stayed through its relaunch as Justice League International, 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. While the League had its serious side and often faced world-threatening villains, it also featured such characters as the lovably inept G'Nort, the worst Green Lantern in the Corps; Mr. Nebula, the interplanetary decorator; the Injustice League, a bunch of bumbling losers; and a flock of homicidal penguins who had been hybridized with piranhas.
DeMatteis stayed with JLI for five years, often scripting its spin-offs (such as a Mister Miracle solo title, or a European branch of the Justice League). DeMatteis also contributed tales of Superman, Batman, Wonder Woman, and Doctor Fate (reinventing the character in a 1980s miniseries with Keith Giffen, which was followed by a series penciled by Shawn McManus) to DC.
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. Spider-Man's battle with the Goblin continued in The Osborn Legacy in #189 and came to an end when Harry died in The Best Of Enemies! (#200).
In the mid-1990s, DeMatteis took over from David Michelinie as writer of The Amazing Spider-Man for a run that included the apparent death of Peter Parker's Aunt May and the beginnings of the "Clone Saga" arc. DeMatteis as well worked on such characters as Doctor Strange, Daredevil, Man-Thing, and the Silver Surfer.
DeMatteis helped launch DC's mature-audience Vertigo imprint, writing the graphic novels Mercy and Farewell, Moonshadow (a sequel to the Epic Comics series), the miniseries The Last One, and the 15-issue series Seekers Into The Mystery, the story of a Hollywood screenwriter on a journey of self-discovery and the search for universal truths.
DeMatteis wrote an autobiographical, digest-sized miniseries Brooklyn Dreams, published by DC's Paradox Press imprint. DeMatteis' most personal work, it was later collected in one volume under the Vertigo imprint.
In the 2000s, DeMatteis redefined the Spectre, through the character of Hal Jordan, as a spirit of redemption rather than of vengeance, and in 2003, with Giffen, he revived the Justice League International for the mini-series Formerly Known as the Justice League. The series won Giffen, DeMatteis and artist Kevin Maguire an Eisner Award. The team followed this with "I Can't Believe It's Not the Justice League" arc in JLA Classified and, at Marvel, a five-issue run of The Defenders. In 2006, DeMatteis and Giffen began work on two original superhero comedy series, Hero Squared and Planetary Brigade for Boom! Studios. The two have reteamed yet again with Maguire for DC Comics' Metal Men, the backup in the Giffen scripted Doom Patrol relaunch.DeMatteis later teamed with veteran artist Mike Ploog to create the CrossGen fantasy comic Abadazad (May 2004). The following year, Ploog and DeMatteis announced they were collaborating on a five-issue miniseries, Stardust Kid, from the Image Comics imprint Desperado Publishing. The series moved to Boom! Studios in 2006.
The Walt Disney corporation acquired Abadazad for its Hyperion Books for Children imprint. The first two books in the series ... Abadazad: The Road to Inconceivable and Abadazad: The Dream Thief ... were released June 2006. The third book ... Abadazad: The Puppet, The Professor and The Prophet ... was released in the United Kingdom in 2007, after which Hyperion canceled the series.
In 2008, DeMatteis became editor-in-chief of Ardden Entertainment, guiding the launch of a new Flash Gordon comic book series. In 2009, he wrote a six-issue comic book limited series, illustrated by Mike Cavallaro, The Life and Times of Savior 28, which was released by IDW Publishing in 2009. He also wrote the Metal Men back-up story in the new Doom Patrol and returned to Marvel Comics for a number of new Spider-Man stories. In 2010, DeMatteis reunited once again with frequent collaborator Keith Giffen for a run on the comic book series Booster Gold.
In June, 2010 DeMatteis's children's fantasy novel, Imaginalis, was published by Katherine Tegen Books, an imprint of HarperCollins.
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 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 and Sym-Bionic Titan. He has written unproduced screenplays for Twentieth Century Fox, Disney Feature Animation and producer/directors Chris Columbus and Dean Devlin.
Also a musician, DeMatteis released one album in the late 1990s, How Many Lifetimes?.