*The series is centered around the exploits of Billy, an idiotic and happy-go-lucky boy; Mandy, a deadpan, cynical and cold-hearted girl; and Grim, a Jamaican-accented Reaper. After Billy and Mandy cheated at a limbo match against Grim, he is enslaved in an unwanted permanent friendship with the children.

Grim is miserable in the first days of his servitude, and even fantasizes about killing them multiple times. However, as the time passes, he gradually adapts to the new life, and even grows to care for Billy and Mandy, if only somewhat. Despite this, he retains a love–hate relationship with the two and desires to eventually break free from his servitude.

Billy and Mandy use Grim's supernatural abilities and powers to venture into supernatural locations or environments, such as the Underworld, or the Netherworld, inhabited by an assortment of grotesque monstrous beasts.

The pair also use Grim's enormously strong supernatural abilities or ties with a number of beastly characters to achieve goals or desires for themselves, often with twisted results. Famed fictional monsters including Dracula, the Wolfman, and the bogeyman are also comically depicted in the series.

Supporting characters include Irwin, Billy's nerdy best friend who has a crush on Mandy; Harold, Billy's father who shares his son's stupidity; Gladys, Billy's loving yet mentally unstable mother; Mindy, the snobby, stuck-up, and spoiled queen bee of Billy and Mandy's school; Sperg, the local bully who has a sensitive side; Hoss Delgado, an overly-intense "spectral exterminator" who hunts supernatural creatures; a friendship-seeking demon who later marries Billy's aunt and bears a son, Nergal Jr. ; General Skarr, Billy's ill-tempered next door neighbor who originated in the Evil Con Carne animated series.*