Henson gained recognition for playing a prostitute in Hustle & Flow (2005) and a single mother in David Fincher's The Curious Case of Benjamin Button (2008).

[1] She has also acted in Baby Boy (2001), The Karate Kid (2010), Think Like a Man (2012), Acrimony (2018), What Men Want (2019), The Best of Enemies (2019), and The Color Purple (2023).

[11][13] To pay for college, she worked mornings as a secretary at The Pentagon and evenings as a singing-dancing waitress on a dinner-cruise ship, the Spirit of Washington.

Her first prominent role was in the 2001 comedy-drama film Baby Boy, where she portrayed Yvette, alongside singer Tyrese Gibson.

[20] Henson has guest-starred on several television shows, including The WB's Smart Guy, the Fox series House in 2005, and CBS's CSI: Crime Scene Investigation in 2006.

[6] In 2005, Henson was in the independent film Hustle & Flow as Shug, the love interest of the male lead, DJay, portrayed by Terrence Howard.

[24] Additionally, Henson has been a cast member on several television shows, including Lifetime's The Division and ABC's Boston Legal for one season.

[25][26] In the November 20, 2013 episode, "The Crossing", after co-starring for two and a half years, Henson's character, 'Joss' Carter was killed as part of the series' new storyline.

It was based on true events in the life of a New York woman whose son, Kobe, was abducted by his biological father to South Korea.

[32] In 2015, Henson was cast to headline in the Fox series Empire, a musical drama set in the hip hop recording industry,[33] where she plays Cookie Lyon opposite former Hustle & Flow costar Terrence Howard.

Fox ordered the pilot in May 2014, and the series debuted on January 7, 2015, with positive critical reviews and wide commercial success.

[41] In 2016, Henson starred in the biographical drama film Hidden Figures, a major box-office success nominated for numerous awards, including three Oscars (Best Picture, Best Adapted Screenplay, and Best Supporting Actress for Octavia Spencer) and two Golden Globes (Best Supporting Actress for Spencer and Best Original Score).

In January 2018, she starred in Sony Screen Gems's thriller-drama film Proud Mary, as a hit woman whose life is turned around when she meets a young boy who awakens the maternal instinct she never knew she had.

[42] In March, she starred in the film Tyler Perry's Acrimony as a faithful wife who, after tiring of standing by her husband, is enraged when she believes herself betrayed.

[48] In December 2020, Henson began hosting the talk show Peace of Mind with Taraji on Facebook Watch.

Henson made her singing debut in the film Hustle & Flow, where she provided the vocals for the Three 6 Mafia track "It's Hard out Here for a Pimp".

[59] Henson has appeared in a few stage roles, including a production of August Wilson's Joe Turner's Come and Gone and the Pasadena Playhouse's Above the Fold.

[68][69] In 2014, Henson said that her son had been racially profiled by police and that his car had been illegally searched during a traffic stop in Glendale, California.

A video obtained by the Los Angeles Times showed Marcell had driven through a lighted crosswalk while a pedestrian was crossing, given verbal consent to search his vehicle, and admitted to smoking marijuana two hours before driving.

"[70][71] A supporter of People for the Ethical Treatment of Animals (PETA), Henson appeared nude in an ad for the I'd Rather Be Naked Than Wear Fur campaign in January 2011.

[72][73] She joined PETA again for their 2013 campaign, "Be an Angel for Animals", where Henson posed with her family dog Uncle Willie.