Mignola's arguably most well known work is Hellboy, which first appeared in the Hellboy: Seed of Destruction mini series published by Dark Horse in 1994. Through 2007, he was the writer and illustrator for Hellboy, with Duncan Fegredo taking over illustration duties after that. He also co-writes the Hellboy spin-offs B.P.R.D. and Lobster Johnson.
Mignola was an illustrator for the Francis Ford Coppola movie, Bram Stroker's Dracula. He worked as a concept artist for Blade 2, and as a production designer on Disney's Atlantis: The Lost Empire. He aslo served as producer on two direct-to-video animated Hellboy movies, Sword of Storms and Blood and Iron.