• Angourie Rice as Cady Heron, a teenage girl who transfers to North Shore High School after being homeschooled her whole life in Kenya
• Reneé Rapp as Regina George, a rich and popular mean girl who is the leader of the Plastics
• Auliʻi Cravalho as Janis ʻImiʻike, Cady and Damian's friend
• Jaquel Spivey as Damian Hubbard, Janis's best friend
• Avantika Vandanapu as Karen Shetty, a member of the Plastics
• Bebe Wood as Gretchen Wieners, a member of the Plastics
• Christopher Briney as Aaron Samuels, Regina's ex-boyfriend and Cady's love interest
• Jenna Fischer as Ms. Heron, Cady's mother
• Busy Philipps as Mrs. George, Regina's mother
• Tina Fey as Ms. Norbury, the math teacher at North Shore High School
• Tim Meadows as Mr. Duvall, the principal of North Shore High School
Additionally, Lindsay Lohan, who played Cady Heron in the 2004 film, makes a cameo as the moderator of the Mathletes tournament, while Jon Hamm plays Coach Carr, the school's physical education teacher. Ashley Park, who originated the role of Gretchen in the stage musical, appears as Madame Park, the school French teacher. Connor Ratliff portrays Mr. Rapp, the school literature teacher. Megan Thee Stallion appears as herself during the social media montages in the film. In the same montage, Jazz Jennings has a cameo as a Social Media Friend.

In 2013, Tina Fey announced that a stage musical adaptation of Mean Girls was in the works. The musical premiered in 2017 in Washington, D.C., and later transferred to Broadway at the August Wilson Theatre in 2018. Fey wrote the book of the show, while her husband, Jeff Richmond, composed the music with lyrics written by Nell Benjamin. The show received positive reviews from critics, and was nominated for twelve awards at the 72nd Tony Awards, including Best Musical.

In January 2020, Fey stated that a film adaptation of the stage musical was in active development. In September 2021, Arturo Perez Jr. and Samantha Jayne signed on to direct, making the film their feature film directorial debuts. Paramount Players was also announced to produce the film. It was also confirmed that Lorne Michaels, who produced the original film, would return to produce the musical film under Broadway Video, alongside Fey's Little Stranger.
During the original film's cast reunion on October 3, 2020, Tina Fey shared that fans could be involved in casting actors for the film by sharing their dream cast on the project's website and be featured in the musical film's "burn book". In May 2021, she suggested to Variety that the original cast members of the stage musical would likely not reprise their roles.

In December 2022, Angourie Rice, Auliʻi Cravalho, and Jaquel Spivey were cast in the roles of Cady, Janis, and Damian, while Reneé Rapp, who previously portrayed Regina as the replacement for original Broadway cast-member Taylor Louderman in the stage musical from 2019 until its closure in 2020, would reprise her role.

In February 2023, it was announced that the roles of Aaron, Gretchen, and Karen would be played by Christopher Briney, Bebe Wood, and Avantika Vandanapu, respectively. Briney originally turned down the role of Aaron upon learning about the role's requirement to sing, but eventually accepted it when the songs he was involved in were cut from the film. Fey and Tim Meadows were added to the cast to reprise their roles from the original film, Ms. Norbury and Principal Duvall. Jenna Fischer joined the cast as Ms. Heron, Cady's mother, while Busy Philipps was announced to portray Mrs. George, Regina's mother. Additionally, it was reported that Ashley Park, who originated the role of Gretchen in the stage musical, will have a cameo in the film. In March 2023, Mahi Alam, Connor Ratliff, and Jon Hamm joined as Kevin, Mr. Rapp, and Coach Carr, respectively.

In December 2023, Rachel McAdams revealed to Variety that she and Fey discussed the possibility of a cameo in the film, but it ultimately did not work out. Fey said, "Paramount was like, 'C…

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Jeff Richmond and Nell Benjamin returned to rework their songs from the stage musical for the adaptation, while Richmond also composed the film's score. Alongside Richmond and Benjamin, Reneé Rapp co-wrote, "What Ifs", a new song for Cady, replacing "It Roars" from the stage production. Other songs removed from the original score include "Where Do You Belong?", "Fearless", "Stop", "Whose House Is This?", "More Is Better", and "Do This Thing".
The film's soundtrack was released on January 12, 2024, by Interscope Records. The album features twelve musical numbers from the film, and the track "Not My Fault" by Rapp and Megan Thee Stallion, previously released as a single on December 15, 2023. It is the only song from the soundtrack that is not used as a musical number in the film, and plays during the end credits scene.

The reprises versions of "Someone Gets Hurt" and "Stupid with Love", and the musicals numbers "Laissez Moi Tout" and "Rockin' Around the Pole", were released as part of the deluxe edition of the soundtrack, titled Bonus Track Version, released on February 20, 2024.
• "A Cautionary Tale" – Janis and Damian
• "What Ifs" – Cady
• "Meet the Plastics" – Regina
• "Stupid with Love" – Cady and Ensemble
• "Apex Predator" – Janis and Damian
• "What's Wrong with Me?" – Gretchen
• "Sexy" – Karen and Female Ensemble
• "Someone Gets Hurt" – Regina
• "Revenge Party" – Janis, Damian, Cady, Principal Duvall and Ensemble
• "Laissez Moi Tout (iCarly Theme Song)"† – Damian
• "Kevin G's Rap"†† – Kevin and the Power of 3
• "Rockin' Around the Pole Again"† – Santa's Little Helpers
• "Someone Gets Hurt (Reprise)"† – Janis, Cady and Damian
• "World Burn" – Regina and Female Ensemble
• "I'd Rather Be Me" – Janis and Female Ensemble
• "Stupid with Love (Reprise)"† – Cady, Prom Band and Company
• "I See Stars" – Cady, Prom Band and Company
† denotes songs absent from the standard edition of the soundtrack. †† denotes songs absent from all versions of the soundtrack.