Between 1989 and 1991, Hounsou appeared in the music videos for "Straight Up" by Paula Abdul, "Love Will Never Do (Without You)" by Janet Jackson, and Madonna's "Express Yourself". He also appears in En Vogue's music video for "Hold On".
Hounsou's film debut was in the 1990 Sandra Bernhard film Without You I'm Nothing. He had television parts on Beverly Hills, 90210 and ER and a guest starring role on Alias. Hounsou had a larger role in the science fiction film Stargate.
Hounsou received wide critical acclaim and a Golden Globe Award nomination for his role as Cinqué in the 1997 Steven Spielberg film Amistad. He gained further notice as Juba in the 2000 film Gladiator. In 2004, Hounsou was nominated for the Academy Award for Best Supporting Actor for In America, making him the fourth African male to be nominated for an Oscar. In 2005 he played a mercenary in the movie The Island alongside Ewan McGregor and Scarlett Johansson. In 2006, he won the National Board of Review Award for Best Supporting Actor for his performance in Blood Diamond; he received Broadcast Film Critics Association, Screen Actors Guild Award, and Academy Award nominations for this performance.
Hounsou acted in a supporting role in the 2009 science fiction film Push, as Agent Henry Carver. In 2011, he starred as a French commando in the French film Forces spéciales.
Director Tim Story told IGN that if he were to do a third Fantastic Four film, he would like to have Hounsou as the Black Panther. In November 2008, it was announced that Hounsou would be providing the voice of the Black Panther in the television series of the same name. Hounsou had signed on to play Abdiel in the film version of John Milton's Paradise Lost with Benjamin Walker and Bradley Cooper. The film however was scrapped in early February 2012.
In 2013, he appeared in the comedy film Baggage Claim alongside Paula Patton. He also voiced Drago Bludvist in How to Train Your Dragon 2 and portrayed Korath the Pursuer in the Marvel Studios film Guardians of the Galaxy, both in 2014. He played villains in two 2015 films, Seventh Son and Furious 7, the seventh installment of The Fast and the Furious film series, the latter where he played the role of Mose Jakande, a Nigerian-French mercenary.
On 17 February 2016, it was reported that Hounsou would join the second season of the television series Wayward Pines. Also in 2016, he played Chief Mbonga in The Legend of Tarzan movie.
In July 2018, Hounsou joined the DC Extended Universe, voicing the Fisherman King Ricou in Aquaman (with the character being motion-captured by Andrew Crawford), as well as replacing Ron Cephas Jones as the Wizard Shazam in Shazam! (2019). Also in 2019, he reprised his role as Korath in the Marvel Studios film Captain Marvel.