Merkerson graduated from Cooley High School in 1970. Initially she attended Eastern Michigan University as a dance major, but she transferred to Indiana University Bloomington thereafter. She completed her Bachelor of Fine Arts in theatre at Wayne State University in 1976. She was conferred an Honorary Doctor of Humane Letters from Wayne State University in May 2009 and received the same distinction from the University of Maryland Eastern Shore in 2012, Montclair State University in 2013 and the University of Pittsburgh in 2017.

In 1978, Merkerson moved to Albany, New York, to join a theater company. She later moved to New York City.

Merkerson’s career began to rise after she assumed the lead role in the one-woman play Lady Day at Emerson’s Bar and Grill. That was followed by a her performance as Berniece in August Wilson’s Pulitzer Prize–winning play The Piano Lesson. For that, she was nominated for a Tony Award as Best Featured Actress in a Play. Merkerson 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, James Cameron’s Terminator 2: Judgment Day; and Navy Seals. In 2006, she won a Golden Globe Award, an Emmy Award and a Screen Actors Guild award for her performance in the HBO film Lackawanna Blues. In 2007, she starred as Lola Delaney in the Los Angeles stage production of William Inge’s Come Back, Little Sheba, playing the role made famous by Shirley Booth. In January 2008 the production opened a successful run on Broadway and earned Merkerson her second Tony nomination.

From 1994 to 2006, Merkerson was married to Toussaint L. Jones.

On April 1, 2010, it was confirmed that after 17 seasons, Merkerson would leave Law & Order at the end of the show’s twentieth season. Her departure from Law & Order, which aired on May 24, 2010, was also the show’s final episode. In total, Merkerson appeared on the series for 17 consecutive seasons – 395 episodes — which was more than any other actor associated with the program.

In 2012, Merkerson became the host of Find Our Missing, a reality-reenactment series on TV One which profiles missing people of color. She performed in Steven Spielberg’s 2012 film Lincoln as Lydia Hamilton Smith, housekeeper to Tommy Lee Jones’s character, Congressman Thaddeus Stevens.

In 2014, Merkerson appeared in the Primary Stages production of While I Yet Live, which was written by Billy Porter. In 2015, she joined the cast of NBC medical drama Chicago Med as Sharon Goodwin, Chief of Medical Services. The series was conceived and written by Law and Order creator Dick Wolf, along with Matt Olmstead, Derek Haas and Michael Brandt. Also in 2014, Merkerson became a spokesperson for Merck America’s Diabetes Challenge, to increase Type 2 diabetes awareness among African Americans.

Merkerson appeared on the television series of Dr. Henry Louis Gates Finding Your Roots on February 5, 2019 (Season 5, Episode 5), in which he revealed that she was a descendant of Isaac Hawkins and eight others of the 272 enslaved people who were sold in the 1838 Jesuit slave sale by Jesuit priests. These priests owned plantations on which the enslaved people tilled tobacco; proceeds from the sale were used to pay off the debts of the Jesuit-operated Georgetown College (now Georgetown University).