He got his start in comic books at DC Comics in the late 1970s. After a number of rejected submissions, his first accepted story was "The Lady-Killer Craves Blood", but it would not be published until years later, in House of Mystery #282. His first published story for the company was "The Blood Boat!" in Weird War Tales #70 (Dec. 1978).
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) and I…Vampire in House of Mystery #290 (March 1981).
He briefly wrote the Aquaman feature in Adventure Comics as well.
DeMatteis and artist Brian Bolland produced a backup story titled "Falling Down to Heaven" in Madame Xanadu, DC's first attempt at marketing comics specifically to the "direct market" of fans and collectors.
DeMatteis had long been eager to work for Marvel Comics, and following roughly a year in which editor-in-chief Jim Shooter kept him busy with odd jobs and fill-ins, in 1980 he began writing for Marvel on The Defenders,and had lengthy runs on Captain America, paired with penciler Mike Zeck, and Marvel Team-Up.