When Billy's parents are attacked by an anaconda, Billy suggest visiting boy wizard Nigel Planter, because he can talk to snakes. Planter in fact does not speak to snakes, but to snacks, and instead he asks for Billy, Mandy and Grim's help to win the affections of Huffefnie Pfefferpfeffer, a beautiful witch in the School of Sorcery (and having a striking resemblance to Gladys). Planter tries using a romantic love potion and enchanted chocolates, but they do not work. The guys end up completely forgetting about Billy's parents.

General Skarr buys a home in Endsville and becomes Billy's neighbor. After Skarr invites Billy into his new house, Billy mentions Grim's scythe as ,he strongest and most powerful weapon in the entire universe, and Skarr tries to battle his desire to be evil again. Eventually Skarr steals the scythe but Mandy proves to be even scarier than he is, and takes it back.

When Billy decides he wants to grow up to be like Grim, he says nothing will stand in the way of their friendship. They meet a girl named Blandy, who looks very much like Billy, and Billy falls completely head-over-heels in love with her. When Blandy shows romantic interest in Grim, Billy is struck with mad jealousy and wants Grim out of the picture. Mandy consults Grim's encyclopaedia of monsters and realizes Blandy is actually a creature from another dimension. Despite Blandy showing her true form and leaving, Billy remains madly romantically infatuated with her; but only up until the following episode.

At school, Billy, Mandy, and Irwin look for a club to join. Irwin plans to join the Macrame club to meet girls; Billy inquires on the Junior CIA club, which forcefully recruits him; Mandy joins the "Secret Snake Club", a snake-themed club consisting of three geeks. The nerds reveal that their "secret agenda" is to resurrect Shnissugah, a giant snake which lived hundreds of years ago in Canada, to take revenge against the popular kids, but they lack the power of the Underworld to do so. Mandy calls for Grim, who proceeds to revive Shnissugah through the internet. Billy, as a junior agent of the CIA, stops a criminal plan by Irwin, who was using the Macrame club for personal gain; and Shnissugah turns out to be a tiny, 8-cm (3.14-in) long, harmless snake.

When Billy finally gets a "secret decoder ring" in his Blasto Bits cereal, he receives a holographic message from a strange creature who speaks about finding the "Secret of the Universe" in an abandoned mine shaft. All the other children of Endsville, also with decoder rings, race to the mine to be the first one to get the Secret. The entire effort is revealed to be a trap laid by Lubbermouth, a worm-like creature from Grim's past, who wishes to free herself from the curse of guarding the Secret. When Mindy looks down at the pit, she becomes the new guardian of the Secret and has to stay there forever.

When Billy goes to visit his maternal grandmother and Mandy decides to have the day for herself, Grim finds himself free of the kids to do whatever he wants to do. Since Grim quickly gets bored he goes to visit General Skarr, and lets him take his magical scythe, which Skarr uses to build an army of giant lawn gnomes. Since Grim is so used to having two kids with him when they go on an adventure, he enlists Mindy and Pud'n to help him combat Skarr and retrieve his scythe. Mindy and Pud'n prove to be worthy substitutes but they are scared away by Mandy when she notices the unusual trio

As Billy desires to be "cool" like Sperg, he has an ectoplasmic manifestation coming out of his mouth. The ectoplasm grows full size and turns out to be the ghost of nineteenth-century British poet Lord Byron, who tries to teach Billy to be cool, using elaborate poetry instead of bare muscles. Billy uses a poem to insult Sperg's mother, and Sperg challenges Billy to a duel. Billy and Lord Byron fight Sperg and his gang, but are badly beaten. Byron tells Billy he has been trained in the arts of coolness, and disappears.

As Grim watches the entire season of "My Troubled Pony" (parodying My Little Pony), he learns from Mandy that the show was cancelled and does not have an ending. Grim decides to reap the "Schlubs" (a parody of The Smurfs), 100 creatures that live in Billy's yard, to melt them into gold so he can finance the creation of the series finale. Grim must get past Billy and the aggressive Schlubs themselves, including the single, large female (a parody of Smurfette). After Grim thinks he got the creatures with his scythe, Mandy appears to have used all the gold herself to become rich.

When Billy digs his front yard he finds a frozen caveman, who is actually Fred Flintstone (from The Flintstones), but whom Billy names Jake Steele. Billy tries to acclimate Fred to the modern life but the job is not easy. When Fred is taken to school, he predictably goes out of control, kidnapping Miss Butterbean and running away in Principal Goodvibes' car. The ensuing chase results in Fred crashing into an ice cream truck, becoming frozen again. Instead of reaping him, Billy decides to bury Fred in the yard again. A future is shown where both Billy and Fred are defrosted by brain-eating creatures.

At a father-and-son picnic, Billy re-encounters with his spider "son", Jeff, in a dirty bathroom. Once again, Jeff tries to make Billy love him as a true father does, but Billy remains terrified of all bugs. Mandy tells Jeff he is being too nice, and to get Billy's attention he needs to be meaner. After being coached by Mandy, Jeff finally snaps and ensnares Billy in his spider web, forcing Billy to say he loves him.

When Billy and Mandy are utterly bored, Grim takes them to Underworld's "Circus of Fear". The ringleader, Dr. Fear, notices Billy and Mandy, and tries to recruit them into the circus to attract customers, who would pay to see real, live humans. After they go back home, Dr. Fear captures the two kids, and Grim has to get them back. During the show, Mandy breaks free and in a strange twist of the story, she reveals that the beastmaster, Clortho, is actually Dr. Fear, who in turn is just an earthworm, leaving Billy confused.

When Nergal goes to visit Billy's family (his in-laws) for the weekend, he ends up staying with them over a year. When Billy finally asks his uncle to leave, Nergal says he cannot return home because he is a complete failure, having lost at a board game 599 times in a row against his own family, and experiencing constant disappointment elsewhere. Billy and Grim tell him to not worry about being a failure, but to embrace it. After training with Billy and Grim, Nergal returns home and he finally wins at the board game, but he also makes a crack in the ceiling and his home starts filling with lava.

When Billy's dad gets a promotion at his job, he tells his family they are going to move to another town, starting a dispute between Billy and Mandy over who gets custody of Grim. Grim suggests they settle this in court, and hours later Billy, Mandy and Grim find themselves in the Underworld court, presided by Judge Roy Spleen, and which has Fred Fredburger, an incorrigible dumb character, as a juror.

Billy, Mandy and Grim visit Mighty Moe, an old man who has discovered the secret to add extra years to his lifespan: a good diet and exercise. Mighty Moe decides to publish his secret in a book, and Grim needs to stop him by offering junk food.

When Billy and Irwin want to watch classic giant monsters movies, Grim decides to take them to Japan to see real monsters. They meet the turtle-like Cragorah (a parody of Gamera) who engages in a fierce battle with the three-headed Kittirah (a cat version of Ghidorah). To help Cragorah, Grim transforms Billy into a giant monster too (a parody of Ultraman). Mandy soon arrives with the intent of punishing them all for organizing this expedition without her permission. Controlling Mecha-Gorillasaur (a giant gorilla robot) she defeats Kittirah and beats Billy.

After a trip to the mall, Mandy becomes the spokesperson for Happy Huggy Stuffy Bears, a new stuffed toy in town. After the success of her commercial, Mandy gives away stuffed bears to other children, who start wreaking havoc in the city. Eris, the goddess of chaos, is behind the toys, which mind-control the children into creating chaos. Mandy decides not to share control of the world with Eris, and orders Grim to destroy the toys.

When Billy, Mandy and Grim go to the beach, Billy is swallowed by a whale known as Blubbery Joe, which also houses in her stomach Mister Geppetto and Pinocchio. Tired of not having a real son, Geppetto convinces Billy to be his "real son", while Pinocchio becomes increasingly jealous and is set on eating Billy's flesh to become a real boy and gain Geppetto's fatherly love and affection. Mandy and Grim search for Billy on board Captain Deadwood's ship, who is made of wood and who has been hunting Blubbery Joe for years. Billy, Geppetto and Pinocchio are expelled from Blubbery Joe's stomach, and as Billy needs to go home, Blubbery Joe accepts to be Geppetto's son.

After spilling salt in a restaurant, and not throwing salt over his left shoulder, Billy starts having an unusual amount of extremely bad luck. The next day, Grim analyzes Billy and finds out he has a "Catastrophe Snail" attached to his brain, which is causing him the bad luck.

After Billy's baseball team loses badly against Mindy's, Grim decides to coach them. Mandy is not allowed on the team, as Billy is reluctant to let girls play, although he does not realize Mindy is a girl too. Mandy puts on a baseball cap and, assuming the role of "Manfred", pitches for Billy's team anyway. With additional help from ghoulish players which played in the Underworld Little Leagues alongside Grim, Billy's team wins when Pud'n hits a home run.

While at Sassy Cat Land, the theme park dedicated to Sassy Cat (and to ridiculously long lines), Billy, Mandy, and Grim stumble upon a closed attraction, a futuristic "house of tomorrow". Inside, they find Master-Control, a sentient and autonomous, thinking, feeling artificial intelligence computer program claiming to know everything (and wishing death upon the trio when Billy angers him), and Tom Smith, a tour guide that became trapped in the house when it closed forty years ago. Tom explains that the attraction closed when a kid, actually Billy's dad, annoyed Master-Control with his dumb questions, and the robots started attacking the humans. Billy, Mandy and Grim exit the house unharmed, but Tom misses his opportunity to escape and is left behind again.

When Mandy and Grim go to the warehouse store, Mandy notices that everything seems to be in order, lacking any presence of chaos. Hoss Delgado, spectral exterminator, arrives saying that everything has been that way since he started dating Eris, the goddess of chaos. Mandy assures Delgado he must break up with Eris to restore chaos, but fearing her temper, he is reluctant to do so. After failed attempts by Grim, Mandy, Billy, and Irwin to break their relationship, Delgado finally tells Eris the truth about he wanting to break up, and she complies by turning into a giant insect and devouring him.

Billy, Mandy and Grim go to the beach where Grim falls asleep and Billy buries him in sand. When they leave, Billy only takes Grim's skull, leaving Grim's body to be found by a rich family that take it with them. With his adoptive family, Grim's body becomes a celebrity and refuses to go back with Billy and Mandy. Eventually, Grim's skeleton is reunited with his skull, but instants later it is shattered by dogs.

When Billy and Mandy's school is preparing for a big game, Mindy entrusts the care of the school's mascot, Fluffy Cat, to Billy, to protect him from being kidnapped by the rival team, the Booty Heads. At Billy's house, Fluffy Cat is a disaster, so Billy's mom throws him into the basement, where the cat gets inside Grim's trunk, absorbing its powers. A giant Fluffy Cat appears just before the game wreaking havoc.

When General Skarr tries to get rid of a weed in his otherwise perfect garden, he asks Grim to use his scythe to do the job. Billy drives a lawnmower and ruins the garden; also, the scythe's magic accidentally shoots Skarr, transforming him into a plant-like creature. Using his new plant powers, Skarr rebuilds his garden, and tries to exact revenge on Billy by throwing a party, and attacking him. Skarr gets mulched by a helicopter rotor, but he is reborn as a small weed.

Lord Pain, a fearsome warrior from the Plain of Eternal Suffering, appears in Billy's house looking to serve his master, Grim. Lord Pain is put to clean the bathroom, and is confused as to why Billy and Mandy treat Grim the way they do. Eventually, Lord Pain realizes that Mandy is to be his real master, and prepares mashed potatoes for her.