After accidentally spilling an experiment of Lisa's, Lincoln sets off a chain reaction that unravels the household.
Lincoln is practicing his yo-yo tricks, when his yo-yo flies off of his finger, and into Lisa's bedroom, breaking the beakers on her desk, and spilling their contents. Fearing how angry Lisa might be when she finds out what he did, Lincoln decides not to tell her who did it, asking "What's the worst that can happen?", and removes the evidence from the scene. Afterward, a stray drop from one of Lisa's formulas causes an explosion that blows a hole that exposes Lori and Leni's closet.
While overseeing the damage, Lori finds a signed photo of Bobby on Leni's side of the closet, which Leni claims was her "88-day-iversary" gift that she forgot to give to her. Lori assumes the two have been dating each other behind her back, and angrily disowns Leni. She storms out of the room and slams the door behind her, causing the coat rack in the closet to fall on Leni's head, knocking her unconscious. When she awakens, Lincoln and Lisa discover that the concussion had made Leni even smarter than Lisa, as evidenced when she corrects Lisa on a complex equation she believed she had solved correctly. Feeling that her world has been shattered, Lisa gives up on science and gets a job as a gas station attendant at Flip's Food & Fuel.
Later, Lynn comes home, enraged that she just got kicked off every one of her sports teams due to her failing school (since Lisa no longer tutors her), and angrily kicks her soccer ball, which hits Lola in the face. Lola gets a hideously swollen nose from the hit, which makes her think she looks like a "monster". When Lincoln tries to encourage Lola not to say that, she runs back upstairs in despair but accidentally trips on the last step, causing her to fall face first on the floor, and lose all but one of her teeth, much to her despair. Lincoln tries to convince Lisa to come back, but she refuses, especially when Leni shows up, arrogantly boasting that she won the Nobel Prize for inventing a car fueled by apple juice, and got accepted into Harvard, which she then drives off to.
Back home, Lola has decided to run away to avoid being reminded of her former beauty while Lana, not wanting to suffer like her, decides to walk around in a plastic bubble for her own protection. Meanwhile, Luna records a music video she wrote about her family falling apart. It becomes so successful that Mick Swagger recruits her to join his tour. Lincoln tries to call Clyde to help him fix the insanity he caused, but he can't because now, since Lori broke up with Bobby, she's dating him for the rebound and they are skydiving together, much to Lincoln's disgust. Luan enters Lincoln's room to announce that she's giving up comedy to become an activist, due to watching too much cable news following Luna's departure (since she no longer has anyone to try her jokes out on). She has also liberated all of Lana's pets, who all run wild throughout the house.
While trying to subdue the rampaging animals, Lincoln watches several reports on the news detailing the fates of his sisters; Luna has been kicked off the Mick Swagger tour after destroying her hotel room in a rage, Luan has chained herself to a giant redwood tree, and Lynn and Lola are on the lam after robbing the gas station Lisa works at. Lucy appears, announcing to Lincoln that she is now a vampire from being bitten by Lana's liberated bat, and she turns into one herself. At his wit's end, Lincoln figures that he still has to save his remaining sister, Lily, only to find that she's not in her crib. Instead, Lisa's spilled chemicals have caused her to grow into a giant where she lifts up the roof so she can grab Lincoln and devour him.
Suddenly, everything cuts back to before Lincoln removed the evidence, revealing all the chaos was only Lincoln imagining a worst-case scenario for not telling Lisa. Lisa enters the room, causing Lincoln to confess that he ruined her experiment. However, instead of being angry, Lisa's happy and hugs Lincoln--when Lincoln expresses confusion as to why Lisa isn't mad, she explains that she was actually hoping for something like this to happen as part of an experiment she was doing. Lisa's also happy that Lincoln did the right thing by confessing to what he did instead of lying to her or just not telling her about it. Lincoln's relieved that things are normal in the house, only to see, to his horror, Lori and Clyde riding by on a tandem bike, apparently having gotten married.
Leni drives a car suggesting that she passed her driving test albeit in the fantasy.
Charles appears to be very intelligent due to the fact that he can use a phone and that Lincoln can understand what he said while it occurred in Lincoln's fantasy.
At the end of the episode, Clyde and Lori are riding the tandem bicycle from "Hand-Me-Downer".
Although all of Lincoln's sisters appear in this episode, Lisa is the only sister who "actually" appears (and possibly Lori at the end of the episode, if she isn't another one of Lincoln's hallucinations).
The order in which something negative happens to Lincoln's sisters within his fantasy:
Lori - Disowns Leni, dumps Bobby, and falls in love with Clyde.
Leni - Becomes smarter than Lisa after being hit in the head with a coat rack, becoming extremely arrogant and uncaring in the process, and abandons her family to go to Harvard after winning a Nobel Prize.
Lisa - Gives up her studies and gets a job at Flip's Food & Fuel.
Lynn - Gets kicked off her sports teams for failing her academics, leading her to run away with Lola into a life of crime.
Lola - Gets hit in the face with Lynn's soccer ball and runs away with Lynn into a life of crime after repeatedly injuring herself to the point where she believes she's a hideous monster.
Lana - Protects herself inside a plastic bubble to avoid any injuries.
Luna - Joins Mick Swagger on a world tour, only to get kicked off for trashing her hotel room in a fit of rage.
Luan - Gives up comedy and becomes an activist after watching too much cable news.
Lucy - Turns into a vampire after being bitten by Lana's liberated bat.
Lily - Becomes a giant after being exposed to Lisa's chemicals.
Innuendo: When Luna was interrupted by her video getting more views, she was about to say "Hell".
Butterfly Effect - The title of this episode is a concept that illustrates how small initial differences may lead to large unforeseen consequences over time.
The Brady Bunch - Lola getting hit with a soccer ball, causing her nose to swell, parodies the famous episode "The Subject Was Noses" where the same incident happens to Marcia Brady.
Chatty Cathy - Flip calls Lisa "Chatty Cathy", which was the name of a talking doll from the early 1960s.
AC/DC - Luna making a song about their family going on a highway to "hello" is a reference to the 1979 song "Highway to Hell".
Harvard University - Leni told Lincoln and Lisa that she was heading to Harvard after winning a Nobel Prize.
Three wise monkeys - When Lincoln shouts, "Where did it all go wrong?!", he, Izzy, and the monkey take on familiar poses by the three "wise monkeys"; Izzy imitates Kikazaru (hear no evil), Lincoln imitates Mizaru (see no evil), and the monkey imitates Iwazaru (speak no evil).
Keep Calm and Carry On - On the side of Lisa's table is a parody poster of this motivational quote from WWII reading, "Keep Calm And Do More Calculus".
Thelma & Louise - Lynn and Lola going on a high-speed chase in the desert is similar to the desert chase scene in the 1991 film.
The DirecTV listings mistakenly titled this episode "The Butterfly Effect".
While Lori is reading what's on the picture of Bobby, she reads "To my bodacious babe" even though it really says "For my bodacious babe".
After Leni gets hit in the head with a coat rack, she awakens and is shown with bandages wrapped around her head. But as she is leaving Lisa's room right before Lisa gave up her studies, the bandages are gone.
When Lincoln was about to run away from giant Lily, the yo-yo was on Lisa's desk, even though Lincoln took it away.
Lola repeatedly getting injuries on her face.
Charles trying to make Lincoln confess to Lisa about his accident.
Something happening to one of Lincoln's sisters, after an event for each one.