Mignola was born in Berkeley, California. He began his career in 1980 by illustrating spots in the Comic Reader. His first published piece was in the Comic Reader, a spot illustration of Red Sonja (pg. 9). His first published front cover was the Comic Reader ; Dominic Fortune, the Spirit, and Doc Savage in November 1981.
In 1983, he accepted an inking spot at Marvel Comics working on Daredevil and Power Man & Iron Fist for Marvel Comics, and later worked on titles such as "The Incredible Hulk", Alpha Flight and the Rocket Raccoon limited-series.
After some initial work for DC Comics, such as 1987's Phantom Stranger and The World of Krypton, Mignola began to attract greater notice at DC. 1988 featured several high-profile assignments, including covers for Batman: A Death in the Family and pencilling Cosmic Odyssey, a galaxy-spanning 4-issue mini-epic featuring an ensemble cast of DC heroes, and Gotham by Gaslight, in which a Victorian version of Batman faces Jack the Ripper. The success of that 52-page one-shot inspired DC to launch the "Elseworlds" concept.
Mignola drew covers for several Batman storylines, including A Death in the Family and Dark Knight Dark City.
Through the early 1990s, Mignola worked on covers and backup features for various DC and Marvel comics. Mignola did the art on Wolverine: The Jungle Adventure for Marvel, and, with Howard Chaykin and P. Craig Russell, he worked on Fafhrd and the Gray Mouser and Ironwolf: Fires of the Revolution for DC. He also illustrated the comics adaptation for Bram Stoker's Dracula for Topps Comics, having assisted with design and storyboarding for the Francis Ford Coppola film.