Johanna "Jo" Mitchell is a 17-year-old tomboy, who lives with her father, who works as a race car driver for NASCAR. The first day of school, she explains that she wants to avoid high school drama, and already knows some of the mean-spirited cliques to expect when going to North Shore High School. Then she introduces the school's most popular clique, "The Plastics" (from the first Mean Girls movie). This time "The Plastics" consist of Amanda "Mandi" Weatherly, a rich snobish girl who lives down the street from Jo; Chastity Meyer, a seemingly slow-witted blond with a raging libido who is known to randomly hook up with guys (even those less popular than she); and Hope Plotkin, a snobbish hypochondriac who seems to suck up to Mandi the most.
(These "Plastics" despite the original members who wore sexier clothes and dressed "sluttier". The new "Plastics" are more preppy and wear more floral outfits).
Jo is set to pretty much avoid The Plastics and she then meets Abigail "Abby" Hanover, a tortured artist who is actually neighbors with Mandi (they have been competing since they were little kids because Abby is a lot richer than Mandi's family). Abby tells Jo she is apart of the very small welcoming committee and then a teacher trips, accidentally throwing his shake on Abby. Jo at this point feels very sorry for Abby.
Jo takes a shop class with a boy named Tyler DuPont, and she begins to have a small attraction to him despite his slight sexism, so she proves she can really be one of the guys by taking over the project. Mandi wonders about Jo's status as the new girl in school. Abby later makes her situation worse by parking in The Plastics parking space, and then Mandi and the rest of The Plastics do stuff like smashing lunch in her face, and paint balling her sports car.
Later, Jo gives Abby a ride home and she meets Abby's father, info-mercial king Sydney Hanover. Sydney offers Jo college tuition for being a friend to his lonely daughter. Jo accepts and begins to become closer to Abby. She and Tyler also go on a date, where they kiss, but the car is bugged by a voice recorder and Jo's revelation of how she hasn't had any boyfriends despite moving around alot and also being a virgin is heard. Jo gets angry at Tyler, and a trio of girls who aren't as popular reveal they had sex with the same guy and they wish they waited for sex like Jo has. Abby also tells Jo that Tyler is actually Mandi's step-brother.
After Jo and Tyler are labeled "hottest couple", a dissaproving Mandi begins pranking Jo by messing with her project which affects her acceptance into her dream college, Carnegie Mellon University. Then Mandi goes too far by filling Jo's dad's racecar with coffee and "skinny and sweet" (a type of artificial sweetener "The Plastics" use).
Jo then decides to get revenge on Mandi by having a party at Abby's house the same night of Mandi's birthday party. More people show up to Abby's party and Quinn, a nerdy fellow outcast student, shows some disdain to how un-fancy the party is as opposed to how Mandi would have a party. The Plastics find out about the party and Hope uses some ipecac to put on the pizza served to make the guests throw up. Abby and Jo quickly get rid of the tainted pizza and she serves one slice to Nick, Mandi's boyfriend. Then Jo challenges Mandi leading her to make out with Nick and he vomits all over her dress.
One week later. Jo, Abby, and Quinn start a new clique called "The Anti-Plastics" and The Plastics wage war on them. But in the process Jo's whole look changes, and she becomes almost as shallow and conceited as Mandi. Jo then tries to break up The Plastics by exposing Chastity's make-out spots, making it seem Mandi did it due to only her knowledge of the specific areas. Then the girls scare Hope by sneezing all over her and she decides to go to the spa over the weekend except The Anti-Plastics put green dye in her seaweed facial mask causing Hope's face to stay green for a long period of time and also causing Mandi to not want to be near her, explaining "I don't pick up ogres".
Jo campaigns for homecoming queen and Mandi, in anger, shoves a cupcake in Chastity's face. Tyler later tells Jo if her rude behavior doesn't change, he may break up with her. Jo then tries to give back the money Sydney Hanover gave her to be friends with Abby. While Jo speaks with Sydney, Mandi overhears of this secret, and she reveals it to the whole school. As a result, Jo loses Abby's friendship, loses Tyler as a boyfriend, and suffering betrayal by Quinn. Jo is then questioned by the principal, Mr. Duvall, about some charity money stolen which was found in Jo's back shed. But it was actually stolen by Mandi and Nick who put there to frame Jo for the theft.
In a rage, Jo escalates the war by challenging Mandi to powderpuff football, and it helps when the rest of The Anti-Plastics and Tyler offer to help her and prove her innocence with the help of Elliot Gold, a computer hacker and geek, who hacks into the computer system of Jo's grouchy neighbor, who installed cameras to monitor what happens across the street at her house. The powderpuff football game is won by The Anti-Plastics, and Mandi and Nick are arrested for theft when the images of them planting the money in Jo's shed is shown. At the school's homecoming dance, it is announced that Abby and Elliot have been elected as king and queen (won due to Jo rigging the voting). Jo and Tyler dance and they get back together.
In the concluding scenes, Mandi and Nick have been sentenced to do community service, yet Mandi is allowed to graduate from school since her mother donated a library (as a bribe) to North Shore High, but Mandi was never popular again.
Quinn became the new leader of The Plastics and made a peace deal with Jo and Abby to disban the Anti-Plastics and leave the students at peace until graduation.
Chastity ended up joining an abstinence club after learning the meaning of her name.
Hope braves her fear of germs only to be sneezed on by a jock while getting water from a drinking fountain and she catches swine-flu.
Abby and Elliot became boyfriend and girlfriend and she ends up going to college as an art major.
Tyler goes to a close-by college to be near Jo. To this day, Tyler and Jo are still romanticaly together, and Jo and Abby remain close friends.