She has since starred in The Divergent Series (2015–16), The Shack (2017), Gifted (2017), Instant Family (2018), Luce (2019), Ma (2019), Onward (2020), and Spirited (2022).

[16] Spencer made her film debut as a nurse in Joel Schumacher's A Time to Kill, based on the book by John Grisham.

[17] Other film credits include: Miss Congeniality 2, Never Been Kissed, Big Momma's House, Bad Santa, Spider-Man, Coach Carter, Win a Date with Tad Hamilton!

She has made a number of guest appearances on television series, including Raising the Bar, CSI: Crime Scene Investigation, The Big Bang Theory, Wizards of Waverly Place, Grounded for Life, ER, Titus, Becker, 30 Rock and Dharma & Greg, plus a recurring role on the sitcom Mom.

She is also known for her starring roles as Serenity Johnson on Comedy Central's Halfway Home, and Constance Grady, the amorous INS caseworker on Ugly Betty.

[18] Later that year, she starred opposite Allison Janney in Tate Taylor's short feature Chicken Party.

She also had a role in the American remake of the Danish classic Love at First Hiccup, opposite Scout Taylor-Compton.

Spencer starred in the feature film Herpes Boy, alongside Beth Grant, Ahna O'Reilly and Byron Lane.

Later that year, Spencer's short film The Captain was honored by the CICFF as a finalist for the REEL Poetry Award.

[24] From September 2014 until February 2015, she starred in Steven Spielberg's Fox drama television series Red Band Society.

[28] In honor of Martin Luther King Jr. Day, Spencer bought out a Los Angeles screening of Hidden Figures to treat low-income families that would have been unable to afford to see the film otherwise.

[32] Spencer earned Golden Globe and BAFTA Award nominations for her portrayal, while receiving her third Academy Award nomination in the Best Supporting Actress category, making her the first black actress to receive two consecutive Oscar nods in back-to-back years.

Spencer executive produced and starred as Madam C. J. Walker in the Netflix biographical limited series Self Made, which was released on March 20, 2020.

[36] Spencer starred alongside Anne Hathaway in Robert Zemeckis's horror comedy The Witches, which released on October 22, 2020.

Spencer co-stars with Melissa McCarthy as women who suddenly develop superpowers in the superhero comedy film Thunder Force.