[11] Aduba first garnered recognition for her acting in 2003, when her performance in Translations of Xhosa[12] at the Olney Theatre Center for the Arts earned her a Helen Hayes Award nomination for Outstanding Supporting Actress in a Play.

In 2007, she made her Broadway debut, portraying Toby in Helen Edmundson's adaptation of Coram Boy at the Imperial Theatre.

[19] In 2013, Aduba began portraying Suzanne "Crazy Eyes" Warren in the Netflix comedy-drama series Orange Is the New Black.

She was nominated for Best Supporting Actress – Series, Miniseries or Television Film at the 18th Satellite Awards for her season one performance.

[37] The next year, she starred alongside Maggie Grace in the comedy-drama Showing Roots, and played supporting roles in Tallulah, Steven Universe, and American Pastoral directed by Ewan McGregor.

Aduba played a major role in the 2017 musical animated film My Little Pony: The Movie, voicing Queen Novo, leader of the hippogriffs/seaponies.

[38][39] After Orange Is the New Black ended, Aduba was cast as politician Shirley Chisholm in the Hulu miniseries Mrs. America (2020), opposite Cate Blanchett and Sarah Paulson.

[40] The miniseries premiered on April 15, 2020, receiving critical acclaim, and Aduba won a Primetime Emmy Award.

[41] She was cast to star opposite Lupita Nyong'o in the ultimately unproduced HBO Max miniseries Americanah written by Danai Gurira.

[42] Aduba also was set to star in the fourth season of FX series Fargo, but dropped out due to "some personal family issues".

[46] In 2021, Aduba appeared in the Broadway production of the Lynn Nottage play Clyde's, for which she received a Tony Award nomination.

In 2023, she starred as Edie Flowers in Netflix's Painkiller, a limited series exploring the reasons behind the Opioid Epidemic in the United States.

[47] In February 2023, Netflix announced that Aduba will star in Shonda Rhimes' upcoming White House-set murder mystery series, The Residence.