In 1995, Ellis made her professional acting debut appearing as Ariel opposite Patrick Stewart’s Prospero in a Broadway revival of William Shakespeare’s The Tempest. She later made her screen debut in the episode of Fox police drama series New York Undercover. In 1996 she had the co-leading role in the independent film Girls Town alongside Lili Taylor. During the late 1990s, Ellis also had supporting roles in films Ed’s Next Move, Desert Blue, In Too Deep, and A Map of the World. From 1996 to 1997, Ellis starred as Officer Leslie Joyner in the ABC police drama series High Incident, created by Steven Spielberg. The series was canceled after two seasons. In 1999, she had the recurring role of Sharon Young on the ABC legal drama, The Practice.

In 2000, Ellis starred opposite Cuba Gooding Jr. in George Tillman, Jr.’s drama film Men of Honor. The following year, she played daughter of Samuel L. Jackson’s character in the mystery-drama film The Caveman’s Valentine, directed by Kasi Lemmons and based on George Dawes Green’s 1994 novel of the same name. Also in 2001, Ellis had a supporting part in the critically acclaimed comedy-drama film Lovely & Amazing. In 2002, she had main role alongside Eddie Griffin in the action comedy film Undercover Brother. In 2004, she played Mary Ann Fisher in the Academy Awards-nominated biographical film about musician Ray Charles, Ray. In 2007, Ellis played the leading role in the thriller Cover. The movie received negative reviews. She also appeared in films Freedomland (2006), The Express (2008) and Notorious (2009). She also played Denzel Washington’s wife in The Taking of Pelham 123 (2009) directed by Tony Scott.

On television, in 2002 Ellis had regular role on the short-lived ABC medical drama MDs. From 2005 to 2006, she co-starred alongside Benjamin Bratt in another short-lived drama E-Ring on NBC. She also had recurring roles on Third Watch, 100 Centre Street, Jonny Zero, Justice and True Blood. In 2009, she co-starred alongside Cuba Gooding Jr. and Kimberly Elise in the made-for-television film Gifted Hands: The Ben Carson Story. Ellis also has appeared in a number of Broadway and Off-Broadway theatre productions. In January 2004, she performed in Regina Taylor’s play Drowning Crow, at the Manhattan Theatre Club. In the Spring, 2012 Hampton University semester, she taught entertainment industry courses. She was also featured in a Hampton Players and Company production, “Through the Crack.”

In 2010, Ellis co-starred opposite Wesley Snipes in the action film Game of Death. She played the leading role in the independent film The Tested based on the award-winning 2005 short film of the same name. In 2011, she appeared in the critically acclaimed period drama The Help directed by Tate Taylor, as Eula Mae Davis, one of the maids, for which she received awards as a part of the ensemble cast. In 2014, she played Vicki Anderson in the biographical drama film Get on Up about the life of singer James Brown, also directed by Tate Taylor. As lead actress, Ellis starred in the independent films Money Matters (2011), The Volunteer (2013), Romeo and Juliet in Harlem (2014), and Una Vida: A Fable of Music and the Mind (2014). She also played the leading role in the 2012 television film Abducted: The Carlina White Story.

From 2010 to 2013, Ellis had a recurring role in the CBS series The Mentalist, as Madeleine Hightower. She also played Ashley Judd’s best friend in the 2012 ABC miniseries Missing, and had another role on the CBS procedural, NCIS: Los Angeles. Ellis also starred as one of the lead characters in the 2013 AMC pilot The Divide. When WE tv picked up the show, Ellis left and was recast with Nia Long.

In 2014, Ellis was cast as the lead in the international co-production epic miniseries The Book of Negroes, based on Lawrence Hill’s bestselling 2007 novel. The Book of Negroes premiered in 2015, and Ellis received critical acclaim for her performance. The Hollywood Reporter critic Whitney Matheson praised her performance. “Except for the first installment that focuses on Aminata’s girlhood, Ellis is present in nearly every scene, aging decades and displaying a stunning range of emotion.” Ellis received a Critics’ Choice Television Award for Best Actress in a Movie or Miniseries nomination for her performance. On February 25, 2015, it was announced that Ellis was cast in the ABC thriller series Quantico. She left the series after two seasons in 2017.

In 2016, Ellis co-starred in the historical drama film The Birth of a Nation, based on the story of the 1831 slave rebellion led by Nat Turner. The film also stars Nate Parker, Aja Naomi King, Armie Hammer and Gabrielle Union. Ellis plays the role of Nancy Turner, Nat’s mother, in the film. Also in 2016, she was cast opposite Keke Palmer in the drama film Pimp about life of women on the streets of New York and work in the illegal sex trade. In 2018, she appeared in If Beale Street Could Talk, a drama film written and directed by Barry Jenkins.

In February 2018, Ellis was cast in a leading role on the CBS drama pilot Chiefs. It was not picked up to series. Later, she was cast in the independent drama film Miss Virginia opposite Uzo Aduba and Vanessa Williams. In 2019, she starred in the Ava DuVernay-directed miniseries When They See Us for Netflix. She received Primetime Emmy Award for Outstanding Lead Actress in a Limited Series or Movie nomination for her performance.

In August 2020, Ellis co-stars in the HBO drama series Lovecraft Country based on the novel of the same name by Matt Ruff. She also portrayed Mattie Moss Clark, the mother of The Clark Sisters, in the Lifetime television film The Clark Sisters: First Ladies of Gospel. The film premiered on April 11, 2020 with positive reviews from critics and was the highest-rated original movie for Lifetime since 2016. Ellis was specifically praised by critics, fans, and the Clark Sisters for her performance. Also in 2020, Ellis was cast opposite Will Smith in King Richard, a biopic about Richard Williams.