- Meryl Streep as Miranda Priestly, the editor-in-chief of the Runway fashion magazine
- Anne Hathaway as Andrea “Andy” Sachs, a journalist and Miranda’s former second assistant who becomes the new Runway features editor
- Emily Blunt as Emily Charlton, Miranda’s former first assistant, who is now a senior executive at Dior
- Stanley Tucci as Nigel Kipling, Miranda’s longtime right hand
- Justin Theroux as Benji Barnes, Emily’s boyfriend
- Kenneth Branagh as Stuart Simmons, Miranda’s new husband
- Lucy Liu as Sasha Barnes, Benji’s ex-wife
- B. J. Novak as Jay Ravitz, the finance-bro heir to the Elias-Clarke publishing house
- Simone Ashley as Amari Mari, Miranda’s current first assistant
- Tracie Thoms as Lily, Andy’s best friend
- Tibor Feldman as Irv Ravitz, Runway chairman, owner of its parent company Elias-Clarke, and Jay’s father
- Patrick Brammall as Peter, Andy’s love interest
- Caleb Hearon as Charlie, Miranda’s current second assistant
- Helen J. Shen as Jin Chao, Andy’s assistant
- Rachel Bloom as Talia, Andy’s friend
- Larry Mitchell as Mack, Andy’s journalist friend
- George C. Wolfe as Paul, a Runway editor
- Pauline Chalamet as Ilana Poole, a Runway editor
- Wes McGee as Frank, Emily’s ex-husband
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