Sixteen-year-old homeschooled Cady Heron moves back to the United States from Kenya with her mother and attends North Shore High School. Cady befriends outsiders Janis ‘Imi’ike and Damian Hubbard, who introduce her to the various cliques, and warn her to avoid the “Plastics”, who consist of the insecure gossiper Gretchen Wieners, unintelligent and bubbly Karen Shetty, and manipulative “queen bee” Regina George. Regina invites Cady to join the Plastics; Janis uses this as an opportunity to convince Cady to infiltrate the group for her.
Cady becomes attracted to Aaron Samuels, a senior in her calculus class and Regina’s ex-boyfriend. Cady tells Gretchen and Karen that she likes Aaron, who warn her that he is off-limits as he has dated Regina. Cady goes to Regina’s house with the Plastics, and Regina’s mother finds her old “Burn Book”, a scrapbook the Plastics filled with cruel content about students and staff at the school.
Cady tells Janis and Damian about the Burn Book, and they explain that Janis and Regina were once friends, but fell out after Regina outed Janis as a lesbian to the school. Cady begins to intentionally fail math to get closer to Aaron, who invites her to his Halloween party. Regina discovers Cady’s crush on Aaron and, in a fit of jealousy, flirts with Aaron before kissing him in front of Cady. Realizing Janis was right about Regina, she agrees to commit to her plan to ruin Regina’s reputation.
Cady tricks Regina into eating weight-gain Kälteen Bars to lose weight and replaces her face cream with lard. The trio target Gretchen’s insecurities by having a Candy Cane-Gram sent to Cady on Regina’s behalf, making Gretchen think Cady is Regina’s new best friend. Gretchen reveals Regina’s secrets to Cady, including her cheating on Aaron with football player Shane Oman. Regina’s reputation takes a further hit after a disastrous performance at the Winter Talent Show leads to viral embarrassment. With Regina’s social status plummeting, Cady becomes the new “queen bee”.
Janis invites Cady to her art show, but Cady tells her she has to travel with her mother to Madison. However, Cady later convinces her mother to let her stay home and secretly throws a house party, where she drunkenly admits to Aaron that she has been deliberately failing math to get closer to him. Aaron rebukes Cady for becoming as manipulative as Regina and storms out. Cady follows him out and is confronted by Janis, who calls her out on being as catty as Regina. Cady accuses Janis of being obsessed with her and Janis responds that Cady has become fully Plastic, renouncing their friendship.
Regina discovers she was not invited to the party and that Cady lied about the Kälteen Bars. She adds herself into the Burn Book and deliberately drops it in the school hallway. Upon the discovery, a riot breaks out among the junior girls over the rumors in the book. Principal Duvall and math teacher Ms. Norbury organize the junior girls into the gymnasium to find the source of the book. Ms. Norbury stages a cathartic intervention, encouraging the girls to apologize to each other about their treatment of others. Janis speaks out and reveals the whole plan to take revenge on Regina, who storms out in anger and, during a confrontation with Cady, is hit by a bus.
Cady realizes the damage she has done and takes full responsibility for the book, leading her to be suspended for three weeks. Ms. Norbury offers Cady a way to earn extra credit by joining the Mathletes at state championships and Cady redeems herself after helping the team win. At the Spring Fling, Cady reconciles with Regina and is elected Spring Fling Queen, but snaps the plastic crown and gives pieces out to the girls, telling them they are all special in their own way. Cady apologizes to Janis and Damian, who accept her back as their friend, and makes amends with the Plastics. Cady also makes up with Aaron as they kiss.