This series is a pairing of two separate cartoons. One is about the Grim Reaper, who after losing a bet, is forced to become the playmate of two children. One is Bill, a cheerful, but dimwitted little boy, and Mandy, a cynical, devious little girl. The other cartoon features the exploits of the evil Hector Cancarne, the disembodied brain of a man who plots world domination. Unfortunately, after his body exploded, his brain was placed in a jar and he became forced rely on a thick-headed bear named Boscoe to perform the physical tasks he was once capable of doing himself. Since the preliminary run of the cartoon, the "Evil" portion has peeled off and the exploits of Hector Cancarne is no longer its own cartoon. The series has been re-titled "The Grim Adventures of Billy and Mandy" and occasional appearances of cartoon characters from the preliminary "Evil" portion have made their way into an assortment of episodes.

The episode "Smell of Vengeance" was to have a scene where Hector Con Carne's Stinker Ray attacks the World Trade Center Towers and the people would jump from the buildings, but the scene was hurriedly removed after the terrorist attacks of 11 September 2001.

Billy's Dad:
Son, it's awfully hard to read the paper through your butt.

Continuity: Sometimes the flower of Mandy's shirt disappears.