Merkerson made her television debut as Reba the Mail Lady on Pee Wee's Playhouse, and has appeared on The Cosby Show, among other series. Her single most important television appearance may have been in the first-season Law and Order episode "Mushrooms", in which she portrayed the grief-stricken mother of an 11-month-old boy who is shot accidentally. Her performance was not only memorable to the audience during that key first season, but also impressed the producers enough to select Merkerson to replace Dann Florek as detective squad chief in the series' fourth season.
Merkerson was nominated for a Tony Award as Best Featured Actress in a Play for her performance as Berniece in August Wilson's Pulitzer Prize-winning play, The Piano Lesson and won an Obie Award in 1992 for her work in I'm Not Stupid.Her screen credits include Jacob's Ladder, Loose Cannons, She's Gotta Have It and in James Cameron's Terminator 2: Judgment Day, in which she played the terrified wife of Joe Morton. In 2006, she won Golden Globe, Emmy and Screen Actors Guild awards for her performance in the television movie Lackawanna Blues, her first starring role. In 2007, she starred on stage in Los Angeles in William Inge's Come Back, Little Sheba at the Kirk Douglas Theatre in the role made famous by Shirley Booth, and in January 2008 opened on Broadway in the production. For the revival of Come Back, Little Sheba, Merkerson earned her second Tony nomination.