From 2015 to 2016, she was one of the original ensemble members in Lin-Manuel Miranda's musical Hamilton, and appeared as Jane in A Bronx Tale (2016–2017).

She gained wider recognition for her role as Anita in Steven Spielberg's musical film West Side Story (2021), winning the Academy Award for Best Supporting Actress.

[6] DeBose made her television debut in 2009, when she competed on the TV series So You Think You Can Dance, making it into the Top 20.

In 2013, DeBose played Mary Wilson in Motown on Broadway, understudying the role of Diana Ross.

She left Hamilton in July 2016 and made a guest appearance on the TV series Blue Bloods as Sophia Ortiz.

DeBose played Alyssa Greene in the film adaptation of The Prom, directed by Ryan Murphy, where she was opposite of Jo Ellen Pellman as Emma Nolan.

[12] In March 2021, DeBose released a dance-pop recording and video of Rodgers & Hammerstein's "Shall We Dance" for the album R&H Goes Pop, produced by Justin Goldner and arranged by Benjamin Rauhala.

[13] In 2021, DeBose played schoolmarm Emma Tate in season 1 the parody musical comedy series Schmigadoon!

"[20] David Fear of Rolling Stone wrote, "DeBose...strong contender for Most Valuable Player here, whose energy—in her singing, her dancing, her line-reading, her side-eyeing—could power a metropolitan block.

[23][24] Following her West Side Story success, it was announced that DeBose would host the 75th Tony Awards.

[27][28] She also made a recurring appearance in the fourth season of the HBO science fiction series Westworld.

Despite being described by Variety as “a little out of breath at some points” and that the lyrics "felt clumsy", show producer Nick Bullen defended the performance, claiming it was well received by the live audience and that the criticism was "incredibly unfair" and he "absolutely loved it".

The initiative was created to help young people connect with organizations and charities that advocate for the LGBTQ+ community.

[47] Previously, DeBose was in a romantic relationship with theater props master Jill Johnson.