After being homeschooled for her entire life, sixteen-year-old Cady Heron begins her first day at North Shore High School. She befriends outcasts Janis and Damian, who explain the school's various cliques, warning her about the "Plastics": the insecure Gretchen Wieners, the dimwitted Karen Smith, and the ruthless queen bee Regina George. Cady is unexpectedly invited to join the Plastics, which Janis hopes to use to collect information on Regina, who she accuses of "ruining her life." Later that day, Cady develops a crush on her classmate Aaron; Gretchen warns her that as Regina's ex he is off-limits.
Despite Janis' insistence that Regina is "evil," Cady comes to enjoy hanging out with the group at the mall and writing insulting remarks about their classmates and teachers in a diary called the "Burn Book". However, at a Halloween house party, instead of talking to Aaron on Cady's behalf, Regina kisses him in front of her and resumes their relationship. Feeling betrayed, Cady fully commits to Janis' plan to ruin Regina's life.
Over the following months, Cady, with Janis and Damian's help, manages to turn Gretchen against Regina and trick her into revealing her secrets, break up Regina's relationship with Aaron (and spend time with him by pretending to need math tutoring), and cause her to gain weight by giving her high-calorie snack bars under the pretense that they are diet food. After violating the Plastics' dress code rules by wearing sweatpants, the only thing that fit her, Regina is banished and Cady becomes the new "queen bee".
With her parents out of town, Cady throws a house party. Drunk, she admits to Aaron that she doesn't really need math tutoring, and he renounces her as being no better than Regina. Janis confronts Cady for throwing a party instead of attending her art show, and declares that she has become as plastic as she pretended to be. Meanwhile, Regina discovers Cady's sabotage and pastes her own photo in the Burn Book to frame Cady, Karen, and Gretchen.
Regina distributes photocopies of the book throughout the hallways, inciting chaos. Principal Duvall and math teacher Ms. Norbury gather the female junior students in the gym to talk through their social issues. When Janis reveals her plan to destroy Regina to the students' cheers, Regina storms out and is struck by a school bus, which fractures her spine.
After realizing a comment she wrote in the Burn Book has implicated Ms. Norbury as a drug dealer, Cady decides to take full responsibility for the book, becoming a social pariah. In order to earn extra credit, Cady joins the school Mathletes at the state finals, answering the tiebreaker correctly to win the championship. The team arrives at the Spring Fling dance, where Cady is elected queen. She breaks the plastic tiara and distributes the pieces to others in the crowd, makes peace with those she had wronged, and shares a slow dance with Aaron.
As senior year begins, the Plastics have disbanded; Regina joins the lacrosse team to channel her anger and Gretchen and Karen join their own cliques. Reflecting on the relative social peace that has taken over North Shore High, Cady notices a trio of new "Junior Plastics" and wonders how much longer it will last.
