The movie is about Cady (pronounced as "Kay-dee" ) Heron (played by Lindsay Lohan) who moves to Evanston, Illinois, a Chicago suburb, after being raised in Africa by her zoologist parents. Cady's family moved there after her mother received tenure at Northwestern University. She begins attending North Shore High School, where she meets Damian and Janis. Damian (Daniel Franzese) is "too gay to function," and Janis (Lizzy Caplan) is artistic and somewhat alternative; neither is very popular. Cady is also introduced to the Plastics: Karen Smith (Amanda Seyfried), Gretchen Weiners (Lacey Chabert), and the Queen Bee, Regina George (Rachel McAdams). Unexpectedly, the Plastics invite Cady to sit with them during lunch.
Damien and Janis convince Cady to pretend to be friends with the Plastics so that she can report all the horrible things they say. Cady reluctantly agrees. The scheme becomes more personal when Cady develops a crush on senior Aaron Samuels (Jonathan Bennett), Regina's ex-boyfriend. Karen and Gretchen advise that it is against "the rules of feminism" for Cady to date one of her friend's exes. Meanwhile, Cady's calculus teacher, Ms. Norbury (Tina Fey), tries to convince Cady to join the Mathletes. Both Damian and the Plastics dissuade her from this path, calling it "social suicide."
As part of Cady's initiation into the Plastics, Regina brings her home to meet her younger sister, who imitates things she sees on TV (scantily-clad dancers and girls flashing their breasts), and her youth-obsessed mother (Amy Poehler). The Plastics also show Cady their "Burn Book," in which they have pasted yearbook pictures of girls in their grade and written mean messages about them.
A few weeks later, Aaron invites Cady to a Halloween party. Cady dresses up as a zombie bride (which she calls an "ex-wife") while all the other girls are dressed as Playboy Bunnies. Upon learning that Aaron invited Cady, Regina becomes jealous and convinces him to be her boyfriend again. Cady witnesses them kissing and leaves, turning to Janis and Damian for comfort and an explanation. They concoct a plan to overthrow Regina by eliminating her "technically good physique," her "high-status man candy," and "ignorant band of loyal followers."
Cady also engages in several sabotage plans which all backfire. As Christmas approaches, Cady is inspired to use Gretchen Weiners to access all of Regina's secrets. She makes Gretchen think that Regina is mad at her; Gretchen breaks down and begins spilling information. At the school's Christmas talent show, Gretchen nearly ruins the Plastics' dance routine. Furious, Regina snaps at her and Gretchen finally lets slip a secret Cady can use: Regina cheats on Aaron.
After winter break, Cady, Janis, and Damian attempt to lure Aaron to the projection room above the auditorium, where it is implied that Regina hooks up with Shane Oman. This plan is unfruitful, though it is revealed that Coach Carr also uses the projection room--to make out with Trang Pak, a student. While Cady convinces Regina to eat Kalteen nutrition bars, which help with weight gain (fattening her up), she also gets closer to Aaron. Her primary method of attraction is making herself seem bad at math so that she can ask Aaron for help. Cady cannot stop herself from telling Aaron that Regina cheats on him, and he breaks up with her. He does not, however, immediately turn to Cady and she finds herself going to even greater lengths to attract his attention.
Soon, Regina's reign over the school begins to show cracks while Cady's popularity grows. At the same time, she is failing math and alienating Janis and Damian, though these matters concern her less and less. Cady discovers just how popular she is when the nominees for Spring Fling Queen are nominated: Regina, Gretchen, herself, and Janis, who Damian nominated as a joke.
Cady's final act of sabotage mirrors her first three-way call, initiated by Regina. She conspires to have Gretchen and Karen find out what Regina really thinks of them (Gretchen isn't pretty and Karen is a slut), and succeeds. The next day, Gretchen and Karen turn on Regina and expel her from their lunch table. They turn to Cady as their new Queen Bee. However, her newfound power affects her relationships and drives her to act more like Regina than she realizes.
She becomes a fully-realized Plastic when she lies to both her friends and her parents in order to host a gathering at her house for Aaron. Janis believes that Cady has to go to Madison to see a performance by Ladysmith Black Mambazo and her parents believe that she is at Janis's art show. The small gathering turns into a large house party. Cady drinks too much in attempt to ease her nerves and ends up vomiting on Aaron after confessing that she lied to get closer to him. He leaves in disgust. Regina shows up and finds out from Shane that the Kalteen bars are causing her alarming weight gain. Damian and Janis arrive later, furious that Cady lied to them. Fed up, Janis finally explodes at Cady and tells her that she is a "mean girl."
In the midst of a furious tantrum, Regina places her own picture in the Burn Book and writes her own horrible message. The next day, she brings the book to Principal Duvall (Tim Meadows). As the only girls not in the book are Cady, Karen, and Gretchen, they are summoned to explain themselves. Regina distributes copies of the book's pages throughout the school to sow discord and disgrace Cady. The junior girls explode into a school-wide brawl. The teachers attempt unsuccessfully to break up the fighting; ultimately, Mr. Duvall smashes a fire alarm to set off the sprinklers and orders all junior girls to the gymnasium.
Cady arrives in the gym to find herself personally reviled by every other girl in the room. Mr. Duvall attempts to discuss any "lady problems" the junior class might have, but after one misguided girl opines about her wideset vagina, he hands the reins to Ms. Norbury. Ms. Norbury guides the girls in a workshop designed to get them to openly discuss their problems. Every clique has its share of bitchiness and infighting. Finally, the girls are instructed to read aloud their apologies to one other, then give in to a trust fall. Cady cannot bring herself to apologize without admitting that she wrote the whole Burn Book, though she did write a derogatory entry twisting Ms. Norbury's self-description as a "pusher." Seeing Cady balk, Janis moves to the front of the line and describes the year's scheme to destroy Regina. She exults, triumphant over both Cady and Regina, and dives into the trust fall. Regina runs out and Cady follows. Her apologies are rejected; Regina snaps at Cady that at least she does not pretend to be innocent. As her rant begins to heat up, she is hit by a bus.
The next day, the police search Ms. Norbury's classroom for drugs on the basis of the Burn Book's entry. Cady feels bad and admits to making up the entry. Cady then decides to "suck all the poison out of her life." She apologizes to Regina, whose spine was badly injured in the accident. She admits to her father that she is failing math; he grounds her. She apologizes to Ms. Norbury and resumes excelling in math. As her own punishment, Ms. Norbury makes Cady attend the Mathlete state finals, which is on the same night as the Spring Fling Dance.
At the Mathlete tournament, Cady is selected to break a tie between North Shore and Marymont. As she sizes up her rather ugly opponent, she realizes that making fun of the other girl will not improve her own math skills. She focuses on her own knowledge about the tiebreaker problem and answers correctly, winning the tournament for North Shore. Afterwards, she intends to return home but Ms. Norbury encourages her to go to the Spring Fling.
The Mathletes arrive as Mr. Duvall is annoucing Spring Fling Queen. Cady is stunned to her hear own name and goes onstage to receive her tiara. With her newfound insight, she gives a speech concerning the events of the year. She apologize to everyone, snaps her tiara into small pieces, and throws the pieces into the crowd.
Cady apologizes more personally to Janis and Damien, who forgive her. Aaron also forgives Cady. They dance and share a kiss.
By the start of the next school year Regina's spine has healed. Her physical therapist has taught her to channel all her rage into sports. Gretchen has joined the Vietnamese clique. Karen reports on the weather for the school news. Aaron attends Northwestern, enabling him to continue dating Cady. Janis has found a boyfriend in Kevin Gnapoor, leader of the Mathletes. The cliques are finally at peace.
The film ends on a rather ominous note, hinting at a new generation of Plastics in the new freshman class.