Cady Heron (LINDSAY LOHAN) is a teenager who's entering the public school system for the first time after living in Africa where her parents worked and home-schooled her. After being introduced by North Shore High School Principal Ron Duvall (TIM MEADOWS) and math teacher Ms. Norbury (TINA FEY), Cady gets the scoop on the school and its social structure by student outsiders Janis (LIZZY CAPLAN) and Damian (DANIEL FRANZESE).
Cady thus learns of the various school cliques, including the most popular one, The Plastics, that consists of Regina George (RACHEL McADAMS), Gretchen Weiners (LACEY CHABERT) and Karen Smith (AMANDA SEYFRIED). The snobby and elitist girls take an instant liking to Cady and offer her a coveted seat with them in the cafeteria.
Realizing the Cady isn't like the rest of the Plastics, Janis and Damian think it's a prime opportunity for someone to get an inside look at the inner workings of the clique. That would include Regina's "burn book" that includes all sorts of mean, nasty and disparaging remarks about most everyone at the school.
Cady accepts the undercover mission and things seem to be going smoothly. That is, until she spots hunky Aaron Samuels (JONATHAN BENNETT) in her math class. Gretchen informs her, however, that he's Regina's ex-boyfriend and thus off limits. When Regina then purposefully sabotages any potential relationship between him and Cady, the latter sets out to turn the Plastics' lives upside down. As she does, however, she begins to fall prey to social power that her position in the clique offers.