In her role as Yvette, the strong-willed girlfriend of a perpetual adolescent (Tyrese Gibson) who lives with his mother rather than take care of his own children, Henson caught the eye of critics and was nominated for a Black Reel Award for her performance. Her impressive performance also led to a steady role on Lifetime's "The Division" (Lifetime, 2001-04), a female-oriented police drama that explored the professional and personal lives of female law enforcement officials.

In 2005, Henson made another big screen splash in the urban drama "Hustle & Flow" (2005), where she was recognized with a Best Actress nomination from the Image Awards for the pivotal role of a pregnant prostitute and live-in girlfriend who provides emotional support to a pimp-turned record producer (Terrence Howard). Henson also sang the film's Oscar-winning song, "It's Hard Out Here for a Pimp," raising her profile by performing it at the 2006 Academy Awards.

Re-teaming with Singleton and Howard in the 2005 violent revenge drama "Four Brothers," Henson gave her all in a small but powerful role opposite Andre 3000. She maintained a presence on the small screen with guest parts in "House, M.D." (Fox, 2004- ) and " CSI: Crime Scene Investigation," (CBS, 2000- ) before returning to the theaters with a supporting role in the likable independent romantic comedy, "Something New" (2006), directed by and starring Sanaa Hamri. Revisiting the underworld, Henson had a supporting role as a hitwoman in J Carnahan's stylish but poorly-received crime thriller "Smokin' Aces" (2006) before critical raves were again forthcoming for her role in the biopic "Talk to Me" (2007). In the true chronicle of Petey Greene (Don Cheadle), who transformed from ex-con to influential 1960s D.C. radio host, Henson gave another stand-out performance as Greene's assertive and supportive girlfriend, earning another Image Award nomination and enthusiastic reception from film critic Roger Ebert, who singled her out as "an unstoppable force and immovable object rolled into one."

In the fall of that year, Henson returned to series television to join the cast of ABC's multiple Emmy-nominated law dramedy, "Boston Legal" (ABC, 2004-08), playing a new addition to the Crane Poole & Schmidt law firm. Following an appearance in the ensemble cast of the successful Tyler Perry outing "The Family That Preys" (2008), Henson received some of the greatest praise of her career for "The Curious Case of Benjamin Button" (2008). Loosely based on the short story by F. Scott Fitzgerald, the David Fincher-directed film chronicled the reverse life of a man (Brad Pitt) born elderly who grows younger with time, with Henson co-starring as the adoptive mother who finds the discarded "newborn" on the steps of the nursing home where she works. In a film populated by A-listers, Henson made an indelible impression with her portrayal of the kindly Southerner, earning Best Supporting Actress nominations from the Screen Actor's Guild, the Image Awards and the Critic's Choice awards. But most significantly, Henson received her first-ever nomination at the Academy Awards.

The actress advanced to starring role status in the film adaptation of T.D. Jakes' novel, "Not Easily Broken," where she and Morris Chestnut played a married couple drifting in different directions. After making a few recurring appearances on ABC's surreal drama "Eli Stone" (ABC, 2008) Henson revisited New Orleans, the setting of "Benjamin Button," to shoot "Hurricane Season" (2009), where she starred alongside Forest Whitaker and Isaiah Washington in a drama about a high school basketball team comprised of Hurricane Katrina survivors. Later that year, she landed a supporting role in the crime drama "Once Fallen" starring Ed Harris and Amy Madigan.