She earned recognition for playing Trudy Campbell in the drama series Mad Men (2007–2015), and had her breakthrough starring as Annie Edison in the sitcom Community (2009–2015).

[5][6] Her mother, Joanne Brenner, works at Para los Niños ("For the Children"), a non-profit childcare agency.

[11][12] While being raised by her divorced parents, she occasionally attended a "Christian-Hindu hybrid church" called the Self-Realization Fellowship with her father, while her mother "would always make sure we knew we were Jewish.

[37] In 2016, she starred as Lucy in the romantic comedy film How to Be Single, and as Martha Dunstable in Julian Fellowes' adaptation of Anthony Trollope's Dr. Thorne for television.

[41] Brie noted that since appearing in GLOW and receiving critical praise for it, she has become more focused on taking "meaningful" roles.

[47] In 2020, Brie starred in the acclaimed drama thriller film Promising Young Woman, directed by Emerald Fennell.

[48] Also that year, she wrote, produced and starred as Sarah in the Netflix drama film Horse Girl, which was directed by Jeff Baena.

[49] Brie then starred opposite Dan Stevens in the horror film The Rental, which was directed by her husband Dave Franco.

[55][56][57] In 2023, Brie wrote and starred in the romantic comedy film Somebody I Used to Know with her husband Dave Franco, who also co-wrote and directed it.

[59] In 2023, Brie also voiced the character of Aftershock in the Disney Channel animated series Moon Girl and Devil Dinosaur.

[60] In February 2023, Brie was cast in Peacock's limited TV series adaptation of the Liane Moriarty novel Apples Never Fall with Jake Lacy, Annette Bening, and Sam Neill.

[62] She stars as Macy's Gift Guide in the American department store chain's Holiday 2024 advertising campaign.