It consists of two segments which were eventually spun off into their own series: The Grim Adventures of Billy & Mandy and Evil Con Carne.
After winning a limbo game to save Billy's pet hamster, the two gain The Grim Reaper (voiced by Greg Eagles) as their best friend for eternity and come across many supernatural or otherworldly characters and locations throughout the series.
Its sister show, Evil Con Carne, follows the brain of a playboy who wants to rule the world with his general, Skarr, and his lover, Major Doctor Ghastly.
His greatest fears were combined by Horror's Hand into a monstrous clown-spider-mailman hybrid in the Big Boogey Adventure movie.
A yellow marshmallow bunny named Bun-Bun used to sneak into Billy's room when he was a baby and tormented him with real spiders.
She also possesses a strong lust for power as revealed in an episode providing insight to the future of the town of Endsville, in which Mandy has enslaved all of its citizens and evolved herself into a large, anthropomorphic being resembling a giant caterpillar (a reference to the Dune series), and Grim's abilities have helped her gain access to satisfaction of her desires.
Mandy smiling is shown to be the end of the world; in the episode "My Fair Mandy", after entering a local beauty contest against the queen bee of her classroom, it was revealed that all of reality would be humorously, psychedelically distorted, resulting in the series swapping premises with that of The Powerpuff Girls, another Cartoon Network animated series.
Despite this, Mandy is seen to crack an evil sneer at the end of a few episodes, such as when she becomes the only person left on Earth, and after winning the contest which gave her a servant in Grim.
In 2021, Maxwell Atoms, who has Asperger syndrome himself, confirmed that Mandy is autistic and likened her to "the cold, rational way [he] learned to view the world in order to survive" in contrast to Billy.
The Grim Reaper is the personification of death appearing as a skeleton wearing a black, hooded cloak and armed with a scythe, who serves as a psychopomp between the realms of the living and the deceased.
Unfortunately for the Reaper, the contract legally binds him to them, such that (as revealed in the episode "Hurter Monkey") if he were to ever break his friendship with them prematurely, he would be forced to spend eternity in Underworld Jail (something he doesn't relish the idea of, as he doesn't know what kind of inmates lurk there) as a result of violating his contract.
Grim is slowly adapting to modern life and is usually seen in his free time watching television (mainly horror movies or soap operas).
His adaptation to daily life also leads him to neglect his duties as a Master of the Underworld and, eventually, not even care about who uses his enormously powerful scythe, seeing as how it is constantly stolen.
He also has a bottomless trunk, where all types of dark magical and mystical objects are found; Billy usually abuses them, creating extensive damage, chaos, ruin, death, and destruction.
While it is shown that Grim does care for his scythe, he often makes the mistake of letting Billy (and in rare instances Mandy and Irwin) use it, or loses it in other ways.
Unlike Mandy and Billy, who show no signs of fear for the frightening, supernatural and magical beings and settings around them when using Grim's magic to venture into the underworld (Mandy because of her fearless yet sinister personality and Billy because of his ignorance and stupidity), Irwin has displayed more signs of cowardice in such situations and seems to be more easily terrified than his friends when he accompanies them on such trips (such as in Big Boogey Adventure and Keeper of the Reaper).
Because of being related to such peculiar monsters, Irwin has been shown to possess superpowers which he displayed basically just in a single episode.
In another episode, Irwin uses Grim's scythe to make Mandy into his love-slave and he even mentions that he knows that is wrong, but he quickly disregards this fact.
He then really enjoys his power over Mandy's mind and when Grim and Billy try to take back the scythe, Irwin doesn't give up without a good fight.
Irwin explains that he was born evil, but had a change of heart when his father showed him the meaning of respect, friendship, and love.
After "Evil Con Carne" was canceled, Skarr became a recurring character in The Grim Adventures of Billy & Mandy as a neighbor who wants to go his own ways.
He speaks in a British accent, and is blind in his left eye, and has a scar beneath it, giving Billy the assumption that he is a pirate.
Retired from villainy, due to Evil Con Carne being bought out by a big entertainment corporation (who didn't want any competition for their attempts at world domination), he moves into Billy and Mandy's neighborhood and is constantly struggling with the temptation to return to his evil ways, his debut episodes serving as a parody of Apt Pupil.
Whilst he is no longer a member of Evil Con Carne, Skarr has many weapons and mementos from his past which he stores in his private study.
He possesses one real hand and a mechanical one, the latter of which can seemingly produce any tool he desires, most commonly a metal fist or a chainsaw-launching crossbow.
He resembles Kurt Russell's character Snake Plissken from Escape from New York and his chainsaw hand is inspired by Ash Williams from the Evil Dead series.
In "Everything Breaks", he brings Billy with him to the Plane of Eternal Suffering on Mandy's orders to help cure him of his destructive habits.
Cerberus is Grim's pet demon dog from the Underworld (Voiced by Jess Harnell, Greg Eagles and Danny Mann), with two heads of a doberman and one of a poodle.
He debuts in "Wishbones" where Billy and Mandy find him in Grim's robe due to him forgetting that he was inside while it was in the washing machine.
Realizing that Trykie is indeed evil, Billy reluctantly allows Mandy to destroy it, who does so by repeatedly slamming the garage door on it to the point where it is unable to repair itself.