In 2016, Abdul-Mateen began his acting career with Baz Luhrmann’s musical drama series The Get Down, which premiered on Netflix. His character Clarence “Cadillac” Caldwell is a prince of the disco world. He was praised for his performance in the series.

In 2017, Abdul-Mateen appeared in Shawn Christensen’s drama film The Vanishing of Sidney Hall, in the role of Duane. It premiered at the 2017 Sundance Film Festival.

Abdul-Mateen played a police officer, Garner Ellerbee, in the action comedy film Baywatch along with Dwayne Johnson and Zac Efron, and directed by Seth Gordon. The film was released on May 25, 2017. He also played WD Wheeler, a smart hand-to-hand acrobat partner, in the musical film The Greatest Showman (2017), which also starred Efron, as well as with Hugh Jackman, Michelle Williams, and Zendaya, about American showman P.T. Barnum.

In 2018, he starred in the road trip drama film Boundaries, along with Vera Farmiga and Christopher Plummer, directed and written by Shana Feste; and played DC Comics villain Black Manta in the film Aquaman, which started shooting in May 2017 in Australia. In 2018, Abdul-Mateen was cast in the horror film Us, directed by Jordan Peele, which was released in March 2019. Abdul-Mateen co-stars in the HBO series Watchmen.

In February 2019, it was confirmed that Abdul-Mateen was in talks to star in the Jordan Peele-produced Candyman reboot as the title character, with Nia DaCosta directing. A trailer for the film was released on February 27, 2020, with the film due to theaters on August 27, 2021.

In March 2019, it was announced that Abdul-Mateen was cast in the fifth season of Netflix’s science-fiction anthology series Black Mirror. He won his first Emmy Award for Outstanding Supporting Actor in a Limited Series or a Special in September 2020.