Kirby rose to international prominence with her portrayal of Princess Margaret in the Netflix drama series The Crown (2016–2017), for which she won the British Academy Television Award for Best Supporting Actress.

[7] After attending Lady Eleanor Holles School and being turned down by the London Academy of Music and Dramatic Art (LAMDA), Kirby took a gap year to travel and work in an AIDS hospice in South Africa.

[18] Kirby had a supporting role in Richard Curtis's romantic comedy film About Time, starring Rachel McAdams.

[19] During that time, she made some apparitions in the American film Charlie Countryman, and in one episode of the British TV series Agatha Christie's Poirot.

[20] In the summer of 2014, Kirby played Stella Kowalski in A Streetcar Named Desire, again collaborating with Benedict Andrews at the Young Vic, alongside Gillian Anderson as Blanche Dubois and Ben Foster as Stanley.

Meanwhile, in 2016, Kirby played Elena in Robert Icke's production of Uncle Vanya at the Almeida Theatre, for which she won rave reviews, with Matt Trueman of Variety writing that her performance: "confirms her as the outstanding stage actress of her generation, capable of the most unexpected choices".

[30]During this year, Kirby had three screen roles: she played Zelda Fitzgerald in Genius alongside Colin Firth, Jude Law, and Nicole Kidman; she has the leading role in the sci-fi film Kill Command; and she played in the romantic drama film Me Before You, directed by Thea Sharrock and starring Emilia Clarke and Sam Claflin.

On the big screen, she starred in two action franchise films: Mission: Impossible – Fallout (2018) opposite Tom Cruise and Fast and Furious: Hobbs & Shaw (2019) alongside Dwayne Johnson and Jason Statham.

For her role in Hobbs & Shaw, Kambole Campbell thought that: "Vanessa Kirby steals the show with wry wit and casual lethality".

[37][38] Peter Debruge wrote for Variety that "[...] this is ultimately Kirby's movie, as the stage marvel [...] delivers her most impressive screen performance to date".

[50] Between 2021 and 2023, Kirby was one of the hosts of the True Spies podcast, alongside Hayley Atwell, Sophia Di Martino, and Daisy Ridley.

[53] The Son had its world premiere at the 79th Venice International Film Festival, and despite the mixed reviews from critics of the movie, the performances of Jackman and Kirby were praised.

[58] In February 2024, Kirby was cast as Susan Storm / Invisible Woman in the Marvel Cinematic Universe film The Fantastic Four: First Steps which is scheduled to be released on July 25, 2025, as part of Phase Six of the MCU.

[60] In March 2024, Kirby was announced as Lynette, the leading role in the Netflix adaptation of The Night Always Comes based on the Willy Vlautin novel of the same name.