[5] They lived on a ranch in Missoula, Montana and moved to the Biltmore Forest suburb of Asheville, North Carolina, when Margaret was four.

[9][10] As a teenager growing up in Asheville,[11] Margaret and her sister were both debutantes; they made their debuts at the Bal des débutantes in Paris.

"[7] Qualley later changed her focus to acting and attended London's Royal Academy of Dramatic Art summer program.

[25][26][27] Qualley first appeared on screen in 2013 playing a small part in Gia Coppola's film Palo Alto.

[32] In 2015, Qualley appeared in the short promotional film L'Américaine for American fashion label Tory Burch.

[38] In Novitiate, Qualley starred as Sister Cathleen, a young woman who begins to question her faith as she trains to be a nun.

[41] She also appeared in the music video for Soko's 2017 single "Sweet Sound of Ignorance" alongside her sister Rainey.

[42] In 2018, Qualley appeared in Donnybrook, directed by Tim Sutton and co-starring Jamie Bell and Frank Grillo.

She appeared in Quentin Tarantino's period comedy-drama film Once Upon a Time in Hollywood (2019), playing a member of the Manson Family named Pussycat.

[56] In the same year, she appeared in director Yorgos Lanthimos's surrealist fantasy film Poor Things, along with Emma Stone and Mark Ruffalo.

[57] In 2024, Qualley and Geraldine Viswanathan starred in director Ethan Coen's comedy road film Drive-Away Dolls.

with Aubrey Plaza and Chris Evans, and John Patton Ford's upcoming black comedy thriller Huntington with Glen Powell.

[65] She began dating actor Shia LaBeouf in 2020 after they were co-stars in Rainey's music video "Love Me Like You Hate Me".

[66] Qualley and LaBeouf's relationship ended in January 2021 after he became the subject of several controversies,[67] including a lawsuit for sexual battery and assault brought by his ex-girlfriend, singer FKA Twigs.