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.

As Billy is tired of all the rules in his house, he cannot resist the urge to try his father's new motorcycle. The motorcycle breaks down, and Billy asks Grim to repair it. Grim's scythe turns the motorcycle into a wild, supernatural vehicle, which transforms Billy's parents and everyone around it into undead creatures and motorized monsters. Mandy makes Billy tell the truth about breaking the motorcycle in the first place, at which point his parents and everyone else return to normal.

When Billy gets under his house's foundation, he encounters again his "son", Jeff the Spider, who has just laid eggs. Jeff tries to make things right with Billy so he can take care of the baby spiders, as he is going to die after the eggs hatch. Naturally terrified of seeing Jeff, Billy runs away and a wild car chase ensues. The eggs hatch, and Grim decides to refill Jeff's hourglass that represents his lifetime so he does not die and can continue to scare Billy.

When Billy, Mandy and Grim notice things have been disappearing in the house, they set out to investigate using a supernatural detector. They find the culprit is a talking "taking tree" in Billy's yard, who has been stealing objects since Billy's dad was a child. To make the tree happy, Mandy and Grim set out to trade the stolen belongings for a highly-valued Mickey Munchle baseball card, which is worth eleventy million dollars. Mandy and Grim return from the baseball shop with the real Mickey Munchle. The tree returns all of the stolen things, but keeps the player.

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 and Irwin start making prank calls, everybody knows that Billy is behind the calls because every telephone has a caller ID. While Billy searches in Grim's trunk in the basement for something to defeat the caller ID, he finds a skull-shaped phone with no caller ID. Grim warns him to not use the phone, because it is used to call the ancient demon Cthulhu, whose sole appearance makes people go mad, and if awakened will cause the destruction of the world. Despite Grim's warning, Billy and Irwin use the phone anyway, and they are sucked into it by tentacles.

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.

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.

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.

When Billy destroys Grim's favorite childhood toy, Fancy Jake, Grim feels devastated and wishes he had never lost the limbo game that made him become Billy and Mandy's best friend forever and ever. A lawyer appears saying that although the game is legally binding while all parties remain on Earth, it is not if Grim leaves Earth. In consequence, Grim follows the lawyer's advice, opens a mystical portal, and leaves. With Grim traveling aboard his spaceship, the lawyer takes off his disguise and introduces himself as Morg, the Martian Grim Reaper, who is also Emperor of Mars and commands an army of Martian, brain-eating zombies.

When Grim decides to visit again his childhood idol, the aged king of the vampires, Dracula, the latter suggest they drive to an early bird buffet, only to get lost in the scorching desert. Grim and Dracula need to find their way back home while dealing with situations like meeting a creepy truck driver and being attacked by a giant scorpion. After what they have gone through, and thinking that Dracula is just a selfish, old man, Grim decides to go a separate way. After finding that Dracula in fact helped him by sucking out the scorpion's venom, Grim rushes to help Dracula, and they finally make it to the diner. However, it appears that Dracula left without paying the check.

As Billy and Mandy celebrate Father's Day, Grim becomes very depressed that he sits inside Billy's closet only listening to country rock music. Grim explains that, since his own father cared more about country rock than his own son, he has been living a lie; telling his father he is a famous country rock singer, and not the actual Grim Reaper. Mandy arranges for Grim's father to come visit and she tells him the truth, but still the old man does not believe her. Grim decides that the only way for his dad to listen to him is while performing country music. At an outdoor concert, Billy, Mandy, and Grim start performing a country rock song, in which eventually Grim reveals his supernatural abilities as the mighty Grim Reaper to his father. Grim's dad accepts his son is the Reaper, but he still does not forgive him for lying to him.

When Mandy says even a trained monkey is more competent to do cleaning chores than Grim, and would complain less, Grim makes Dickie Galoot, a monkey appearing in a Japanese-styled animation, come to life to prove her wrong. As Dickie turns out to be extremely good at cleaning Mandy's house, Grim decides to leave the kids for good. Due to his friendship contract, Grim is unable to break free, and he is forced to battle Dickie to recover his place as the "cleaning monkey" of the group. Grim successfully defeats Dickie at cleaning Billy's house, but this all turns out to be an ingenious plan devised by Mandy to win a bet against Billy.

At a school fair, Grim's scythe accidentally transforms the dull Principal Goodvibes and his hippopotamus into gangster rappers, Goodvibes now calling himself Principal Goodbling. In the following, Goodbling changes the entire school to be more hip-hop-oriented, to the annoyance of Mandy. Although initially Grim likes the new style of the school principal, he later thinks Goodbling is just a poseur and goes to talk to him, but Goodbling attacks with yo-mama jokes. Irwin's grandmother, Tanya, confronts Goodbling and proves to be better than he is at yo-mama jokes that Goodbling reverts to being the boring Goodvibes.

When Billy finds his "son" Jeff the Spider lying in his bed with "Spider Pox", he goes to Mandy for help to get rid of the giant spider. While ignoring Billy, the next morning Mandy awakens afflicted by Spider Pox too, developing four additional arms and the ability to produce spider web. Mandy's condition progresses and she completely turns into a giant spider, who captures Billy's parents and Grim. Grim tells Billy that, to cure Mandy, he must use the venom of the spider that infected her. While Billy successfully gives Mandy Jeff's venom, he also carried the virus and infected the people of the city, who have all turned into spiders.

When Billy, Mandy and Grim once again go to the beach, Grim warns Billy to avoid swimming too far, because the "undertoad", a frog-like creature, will try to drag him into the sea. Billy encounters the undertoad, and he barely makes it back to the beach. With the dangers of the sea averted, the guys go back home, but the undertoad is set on bringing Billy down, that he follows him to his house. The next day, the undertoad becomes a constant annoyance to Billy, even at school. Grim and Mandy capture the undertoad, and set sail to release him at sea, where they meat the giant Mama undertoad.

A scene of Endsville two weeks into the future shows a dystopian world ruled by the "Lord of Horror", who wields the all-powerful artifact known as "Horror's Hand". At the same time, two robotic replicas of Billy and Mandy are sent into the past, to stop the real Billy and Mandy from interfering with the current events.orror's Hand to rule the world.

When Billy accidentally food-poisons Miss Butterbean, Principal Goodvibes offers Grim the job of substitute teacher, which Grim accepts as now Billy and Mandy have to obey him. Grim sends misbehaving students to the "Detention Dimension", a place of eternal classroom punishment, until only Mandy remains in his class. Grim tricks Mandy into opening a portal and she is dragged into the dimension too. Mandy proves to be more terrifying than Miss Slither, the giant, rattlesnake-like creature in charge of the Detention Dimension, that Mandy escapes the place and takes revenge on Grim by sending him there too.

When vampire hunter Lionel Van Helsing prepares to kill Dracula, Billy, Mandy, and Grim arrive to stop him since Dracula is just senile and harmless. Van Helsing reveals the source of his hatred: in the past, he and Dracula were "best friends forever", until Dracula used his irresistible dance moves to marry Tanya, the woman of his dreams. Tanya arrives too, revealing that she is none other than Irwin's grandmother, making Irwin one-quarter-vampire on his father's side and half-mummy on his mother's side. Van Helsing leaves, but Dracula is unsatisfied with his newfound family of nerds.

When Grim cannot take any more abuse from Mandy, Billy tries using Grim's scythe to shrink her to mouse size. Instead of shrinking, Mandy becomes a giant and destroys Billy's house. Although Mandy enjoys being a giant for a while, there are inconveniences, as she keeps growing as time passes, and she wants to return to her normal size. Billy is the only one who can cancel the curse he put on Mandy, and he refuses to do so. Mandy grows bigger than the planet, and she finds herself in the "Realm of the Infinite" with other creatures that grow at infinite pace. Mandy starts bossing them around to please her.