The home-schooled daughter of zoologist parents (Ana Gasteyer and Neil Flynn), Cady Heron (Lindsay Lohan) is unprepared for her first day of public high school at fictional North Shore High School in Illinois. With the help of social misfits Janis Ian (Lizzy Caplan) and Damien (Daniel Franzese), Cady learns about the various cliques, including the Plastics, an exclusive group of girls led by queen bee Regina George (Rachel McAdams), who was once Janis' best friend. Janis hatches a plan for Cady to infiltrate the Plastics and get revenge for what Regina did to Janis in 8th grade. Along the way, Cady learns about the "Burn Book," a top secret notebook filled with rumors, secrets and gossip about the other girls in school, and falls for Regina's ex-boyfriend, Aaron Samuels (Jonathan Bennett), who sits in front of her in calculus. She convinces Regina to eat a high-calorie bar that her parents had given kids in Africa to help them gain weight, telling her that they will make her lose weight.
In her efforts to get revenge on Regina, Cady gradually loses her individual personality and remakes herself in the image of Regina. Soon, her act becomes her reality, and she becomes as mean as Regina. Cady perceives the machinations of the high school students to be akin to the struggles for dominance among wild animals.
Eventually, Regina, upon discovering the truth about the bars she has been eating, strikes back by spreading the contents of her "Burn Book," around the school, which ultimately causes a riot as the class learn all of the nasty things others have been saying about them. Called into the gym, the girls are forced to listen to one of the teachers, Ms. Norbury. She makes the girls realize that all of them have been hurt by having mean things said about them, and all of them have said mean things about others. She has each girl confess and apologize to the rest of the girls. Janis confesses her plan to destroy Regina, causing Regina to storm out and get hit by a bus, for which the school blames Cady. Cady has lost all of her friends, her status, the guy she had a crush on, she's failing math, and her parents punish her. Cady also wrote a rumor that Ms. Norbury dealt drugs in the Burn Book, and, because another rumor in the book about a teacher turned out to be true in turn, learns Ms. Norbury will likely get fired. Cady then begins to try to make amends. She confesses what she did in order to get Ms. Norbury exonerated, and in order to make up for her failing math grade, she joins the Mathletes Team.
At the Spring Fling dance, Cady, in her Mathletes uniform, makes up with her true friends, and reaches a truce with the Plastics. She is elected the Spring Fling Queen, and gives a speech to her class that they all deserve it and are all wonderful in their own way. She distributes the pieces of her crown to her fellow classmates, and makes up with Aaron.
The Plastics break up, though. Regina returns to school and joins the lacrosse team as a way to channel her aggression; dimwitted, blond Karen (Amanda Seyfried) becomes the local weather girl; follower Gretchen (Lacey Chabert) joins the "Cool Asians" clique; and Cady stays on the Mathletes and continues to date Aaron. Regina and Cady have gained mutual respect for each other, and Janis is dating Cady's fellow Mathelete Kevin Gnapoor (Rajiv Surendra).
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