Elmyra is chasing after Babs and Buster Bunny, until she crashes into the camera, and bunnies hop around her head. As Babs and Buster are panting from being tired, they see Furrball run from a giant pitbull dog (not Arnold), and Furrball himself moves Buster out of the way and back as he hides in a tree. As the pitbull moves Buster out of the way, Furrball uses a squirrel to spit acorns at him and runs off again. Now, Elmyra has found them from the tree and chases after them again until they hide in her mailbox. She wishes she had bunnies, but admits that ("at least") she still has other animals.
Meanwhile, on a dog, which is scratching, a family of Italian fleas (consisting of Flio, Itchy, and their parents, are eating a bit of dog, so Elmyra puts flea spray on him. They hear a flea spray alarm, and move away. But they stop when they arrive at the flea collar the dog is wearing, so they later jump on the pitbull (except for Flio, who lands on Furrball, whose tail is caught in the pitbull's mouth.) Both animals scratch, but the pitbull is still biting Furrball's tail. Realizing Flio isn't with them, his family calls him. Flio hears them and tells them that he's on Furrball. By this point, however, the Pit Bull lets go of Furrball's tail, and Furrball runs away, scratching. Flio calls for his family again, but now he is far way from them. The rest of the family, still on the Pit Bull, call for Flio again, but to no avail. The pit bull then tries to get them off his back by biting at them, with no success.
That evening, Furrball crawls back to his cardboard box, looking for something to eat. He picks up a brick and notices a speck underneath it. He picks up the speck and looks at it through a magnifying glass, but to his dismay, it's only a piece of dirt. Flio, who is still on Furrball's fur, is sad, because he is alone. Furrball starts to itch again and tries to scratch, but as he scratches, Flio begins to sing about how alone he is, and how much he misses his family. Furrball looks at him with his magnifying glass, and is about to pull him off his fur with a fork, but having heard his song, he decides to let him stay. All the while Flio sings, Furrball itches, and tries to scratch. Flio then moves from Furrball's back to the top of his head, and it begins to rain, so Furrball takes shelter in his cardboard box. Flio finishes his song, and Furrball decides to let him stay on his fur. After Flio finishes his song, a bird holding a tissue, nested on a telephone pole says, "Heartbreaking, isn't it?"
As Furrball sleeps, Flio tells him, "Good night, sleep tight, and don't let the bedbugs bite!". At that very moment, a hungry Bedbug burrows his way to Furrball's fur. He decides to search Furrball's fur for a flea to eat.
In the second act, Flio is sleeping on a patch of Furrball's fur the next morning, when the Bedbug sneaks up behind him. The Bedbug wakes up Flio, who is now frightened. Flio runs away as the Bedbug chases him, and Furrball wakes up, still as itchy as ever. First, he stops by a pet store, where he finds out they are having a porcupine sale. He goes inside the store, scares a porcupine, and uses the porcupine to scratch himself. However, the manager of the store is not pleased and promptly kicks Furrball out. Furrball then stops by the Acme Lumber Mill, where a worker is using a sander to flatten a plank of wood. Furrball pokes the worker, who briefly turns his back as Furrball climbs up to lay down on the plank of wood. Furrball enjoys having the sander scratch his back, but his enjoyment is short-lived, as the worker promptly tosses him onto a conveyor belt. On the other side of the conveyor belt is a saw that splits logs in half. Ordinarily, Furrball would be concerned about it, but today, he was too itchy to care, and hoped the saw would scratch his back. The worker then shuts off the conveyor belt and the saw, and kicks Furrball out of the Lumber Mill.
Not far away, the Pit Bull passes by Furrball, with the rest of the Flea Family still on him. Papa calls for Flio, on the lookout for Furrball. Mama asks him if they found Furrball yet, and he tells her he hasn't, but he has seen a Scottish Terrier up ahead. As the Scottish Terrier passes by, Papa asks the Scottish Flea, who is playing golf, if he has seen Furrball or Flio. The Scottish Flea tells them he hasn't, but he'll keep looking. The Scottish Flea then hits the ball, which flies into the Scottish Terrier's ear, which he proclaims as a hole-in-one.
The Pit Bull comes up to two dogs, a slim green one, and a fat purple one, and while the Pit Bull battles the slim green dog, Papa and Mama ask the British Flea on the fat purple dog if they've seen Furrball or Flio. The British Flea tells them he hasn't seen either of them. Mama is worried about Flio, but Papa tells her that they will find him.
Meanwhile, Buster and Babs are being chased by Elmyra at Acme Looniversity. The two bunnies outrun her and manage to lose her behind a pair of wooden doors. Buster decides he and Babs need to trick Elmyra, and he pulls out a wardrobe of disguises. He and Babs each put on a pair of British clothes, and Elmyra opens one of the doors. She is fooled by Buster and Babs's disguises, and asks them if they've seen a pair of adorable bunnies. Buster and Babs point in conflicting directions, confusing Elmyra. While she is confused, Buster kicks her out of their way. Buster and Babs remove their disguises and joke about Elmyra's stupidity. Pac-Man and Ms. Pac-man show up and they feel like having another adventure with Buster and Babs. Furrball then rushes in, itching. Babs tells Buster that Furrball is itching, and Buster decides to douse him with flea spray. Furrball swipes the can of flea spray out of Buster's hand and tells him Pac-Man, Ms. Pac-Man and Babs that the flea on him is his friend. Buster promptly concludes that Furrball needs help if he calls a flea his friend. Pac-Man gets confused as well. Furrball then pulls out a magnifying glass so that the bunnies can see his new flea friend. Flio is still being chased by the Bedbug, who wants to eat him. Pac-Man, Ms. Pac-Man and Buster start to worry about Flio, and Babs asks him what they can do to help him. Buster decides there's only one thing to do.
Pac-Man, Ms. Pac-Man, Buster, Babs, and Furrball stop by the Acme Cartoon Cliche Computer, and Buster looks up "How to Save a Flea". The computer tells him, "Cartoon Cliche #1: Shrink Your Heroes." Babs tells Buster, "It's so crazy, it just might work!", to which Buster tells her that's Cartoon Cliche #2.
At the Acme Student Lab, Buster, Babs, and Furrball are on a platform, as Buster asks Calamity Coyote how his shrinking ray will work. Calamity shushes Buster, and holds up a sign that says, "Magic!". Pac-Man says "You know magic Calamity?" as Calamity holds up a sighn saying "Yes my good Pac-Man." Buster remarks, "The miracles of modern science." Flio then tells his friends to hurry up, as the Bedbug is still trying to eat him. Buster tells Calamity to turn on the machine, but just as Calamity is about to, Plucky stops him and tells him he's meddling in things man was meant to leave alone. As Plucky tells Calamity to think of the danger or how he could be killed, Hamton holds up a sign that says "Cliche #3". Buster then tells Plucky that if their plan works, they'll be heroes. Plucky likes the idea of being a hero and is willing to help Buster and Babs. Ms. Pac-Man then tells Calamity to turn on the machine, and Calamity turns it on. Buster then tells the viewers that his, Pac-Man's, Ms. Pac-Man's, Babs, and Plucky's ten minute mission is to bodily go where no rabbit has gone before. Calamity's machine then disassembles Pac-Man, Ms. Pac-Man, Buster, Babs, and Plucky's molecules and transfers them to Furrball's fur, where they are all now the size of fleas. Buster then pulls out a sword and declares that they've got a flea to find. As he cuts through Furrball's fur with a sword, he begins to worry about where Babs is. Babs swings on a piece of Furrball's fur, giving out a Tarzan yell, then saying, "I can't help myself." As Babs stops, Plucky tells her, "That was unnecessary" but Pac-Man laughs at it. Flio then runs past Plucky, and he tells them he's found him. Flio introduces himself to Pac-Man, Ms. Pac-Man, Buster, Babs, and Plucky, and likewise, Plucky introduces himself, Buster and Babs to him. Flio then tells them that's he's lost the rest of his family, who are on a Pit Bull. The Bedbug then sneaks up behind Flio, but just as he is about to eat him, Babs stops him, telling him he can't eat him now. The Bedbug then asks, "How come?", and Babs tells him to come closer so she can tell him. The Bedbug moves in closer to Babs, and she pokes his eyes with her ears. She then runs off, taking Flio with her.
Furrball walks down the street and runs into the Pit Bull, who promptly chases him. As Furrball runs from the Pit Bull, Flio, Pac-Man, Ms. Pac-Man, Babs, and Plucky hold on to Furrball's fur. Flio tells Pac-Man, Plucky and Babs that that Pit Bull is the same one the rest of his family is on. Furrball then runs into the door of Elmyra's house, and knocks himself out. The Pit Bull then sneaks up behind Furrball as Elmyra opens the door, happy to see Furrball again. She takes him inside and closes the door just in time, as the Put Bull slams into the door and leaves a hole in it.
On Furrball's fur, Flio is upset over missing his family, and Plucky bangs his head up against a piece of Furrball's fur, as he was really close to being a hero. Plucky then continues to bang his head up against Furrball's fur, prompting Furrball to itch. Elmyra thinks that Furrball brought more fleas, and pulls out a can of Acme Flea Dead spray. Furrball is worried that the spray from the can might kill his friends, but to his relief, the can is empty. Elmyra decides to try Plan B: giving Furrball a bath instead. On Furrball's fur, Plucky, who is distraught, asks what he, Buster, Babs, and Flio should do now. Babs tells him, "Run!", as she, Buster, and Flio duck behind some of Furrball's fur. Plucky then asks Babs, "Why don't we areobicize while we're at it?". Babs tells Plucky that aerobics won't help them get away from the bedbug. The Bedbug then scares and chases Babs, Plucky, and Flio away, but Buster stop the Bedbug and puts on a sombrero. He then uses Bugs Bunny's "Slap Dance" technique, but with no success, as the Bedbug slams him down. Buster then says, "That's funny. It worked for Bugs Bunny." Pac-Man says to Buster "Well if only Bugs was here he could help out!"
Elmyra takes Furrball to the bathroom and puts him in the sink. She then turns on the water and tells Furrball not to be scared. Pac-Man, Ms. Pac-Man, Buster, Babs, Plucky, and Flio are now trapped, with water on one end and a hungry bedbug on the other.
In the third act, The Pacs, Buster, Babs, Plucky and Flio are still trapped, but Plucky decides to take his chances in the water, since he is a duck. Plucky then dives into the water and swims away. The Bedbug then pounces at Pac-Man, Ms. Pac-Man, Buster, Babs, and Flio, who move out of the way, and the Bedbug jumps into the water, getting himself washed away. Babs and Flio manage to land on their feet, but Buster slips and falls on his belly. He then remarks, "I meant to do that." A wave from the water splashes over Buster as Plucky, still swimming, tells them that they're up a creek without paddles like his. Buster tells Pac-Man, Ms. Pac-Man, Babs, Flio, and Plucky to follow him to Furrball's ear. They take shelter in the ear, and Plucky begins drumming. Pac-Man Buster tell Plucky to leave Furrball's ear drum alone, and Plucky stops, calling Buster a spoilsport.
Elmyra tells Furrball, "all done!", and Furrball is relieved that his bath is over, or so he thinks. Elmyra then tells Furrball, "Except for the head!", and dunks his head into the water. Inside Furrball's head, Plucky asks Buster what the big, yarn ball-shaped thing hanging inside is. Buster tells Plucky that Furrball likes to play with string, and that the thing must be his pleasure center. As Furrball recovers his head from the water, his pupils turn into a pair of yarn balls, and he sinks his head back into the water. Babs then wonders what the locker next to the pleasure center is, and opens it, releasing a ghost. Buster tells Babs that the locker must be where Furrball's greatest fear is stored. Furrball runs out of the water, and Elmyra asks, "What's gotten into him?".
After Furrball gets out of the water, Buster tells Babs, Pac-Man, Ms. Pac-Man, Plucky, and Flio that they can come out now, as Furrball's fur is as dry as a bone. Buster then steps into Furrball's wet fur and jokes that's it's dry as a bone at the bottom of Plucky's pond. Plucky then plugs his beak and says he hates the smell of wet animal fur. Furrball hides under the couch cushion, but Elmyra catches up to him and tells him that she's going to do him an even bigger favor, and give him a new "besest friend," in the form of "the bow-wow next door" (Obviously referring to the Pit Bull). Furrball hides under the couch cushion, but Elmyra pulls it out. Furrball is scared and refuses to leave, but Buster yells in Furrball's ear, asking him him, "You want to help your little flea pal?", and Furrball agrees with him. Buster then tells Furrball to go outside and confront the canine. Furrball still refuses, but Flio decides to talk to him. He tells him, "Please, Furrball, please!", and Furrball decides not to leaf his flea friend down. He marches outside, and works up the courage to confront the Pit Bull. On the Pit Bill, Papa calls for Flio, and Pac-Man, Buster, Plucky, and Flio call for the Flea Family to join them on Furrball. The Flea Family jumps from the Pit Bull to Furrball, and are happy to see Flio again. The Pit Bull growls at Furrball, as Buster tells Furrball that since the Flea Family made it, he should run. Furrball tries to run, but the Pit Bull has grabbed Furrball by his tail and has pulled him toward him. The Pit Bull then get ready to punch Furrball, as Buster, Babs, Plucky, and the Flea Family await their doom. Flio tells everyone that Furrball is the bravest cat he ever saw. Plucky then tells Flio, "'Was' the bravest cat." Furrball then swipes at the Pit Bull and scratches his nose, scaring him behind some trash cans. Buster then jokes about the Pit Bull being an "Old Yeller", and at first, Furrball is proud of his accomplishment, but then he overhears the Pit Bull yelling in pain. Furrball then comes up to the Pit Bull, who doesn't want Furrball to scratch him again, but Furrball is sorry and wants to shake hands with the Pit Bull. Buster, Babs, Plucky, and the Flea Family cheer.
Back at the Acme Student Lab, Plucky tells Pac-Man, Ms. Pac-Man, Buster and Babs that Calamity is ready to revert them back to their original sizes. Papa thanks Pac-Man and Buster, who tells them it was nothing. Babs then asks Mama where she and her family are going to live now. Mama tells her that they've made arrangements with Furrball. The Flea Family waves good-bye as Calamity reverts Pac-Man, Ms. Pac-Man, Buster, Babs, and Plucky back to their original sizes. Plucky is disappointed when he comes back, as there's no press, and he, Buster, and Babs have just returned heroes. Buster tells Plucky in an italian accent, that Furrball is a lot braver now. An itchy Furrball waves good-bye to Buster and Plucky as Flio sings about being reunited with his family on their new home in Furrball's fur.