Hounsou was born in Cotonou, in what is now Benin, to Albertine and Pierre Hounsou, a cook. He immigrated to Lyon in France at the age of twelve with his brother, Edmond. Soon after arriving in France, Hounsou dropped out of school and became homeless for a time. A chance meeting with a Photographer led to Hounsou being introduced to fashion designer Thierry Mugler, who encouraged Hounsou to pursue a modeling career. In 1987, Hounsou became a model and established a career in Paris. He moved to the United States in 1990.

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 captured 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 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.

On February 24, 2007, it was announced that Hounsou would be the new Calvin Klein underwear model. At the time, Hounsou was being represented by Los Angeles modeling agent, Omar Albertto.

Director Tim Story told IGN that if he were to do a third Fantastic Four movie, 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 2007, Hounsou began dating model Kimora Lee Simmons. On May 30, 2009, Simmons gave birth to their son, Kenzo Lee Hounsou, meaning "Three" (Kimora's 3rd Child). Hounsou and Simmons visited Hounsou's family in his native Benin in the summer of 2008, where the two participated in a traditional commitment ceremony. The couple were adorned in traditional clothing and used the ceremony, in the presence of Hounsou's family, to solidify that they are "dedicated to each other 100%." The two, however, emphasized that the ceremony was not a wedding. In the début of Kimora Lee Simmons' show, Kimora: Life in the Fab Lane, he was billed as her husband. Hounsou and Simmons, who were never legally married in the United States, announced their separation in November 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 February 17, 2016, FOX reported that Hounsou would join the second season of the television series Wayward Pines.