Away from film, Mackie has performed in Broadway and Off-Broadway adaptations, including Ma Rainey's Black Bottom, Drowning Crow, McReele, A Soldier's Play and Carl Hancock Rux's Talk, for which he won an Obie Award in 2002.

[6][7][8] His brother, Calvin Mackie, is a former associate professor of engineering at Tulane University who now works at the Louisiana Recovery Authority.

[10] He later graduated from the Juilliard School's Drama Division as a member of Group 30 (1997–2001), which also included actors Tracie Thoms and Lee Pace.

The following year, Mackie appeared in Million Dollar Baby, which won the Academy Award for Best Picture, and starred in Spike Lee's She Hate Me.

He appeared in the 2011 film The Adjustment Bureau as Harry Mitchell, a sympathetic member of a shadowy supernatural group that controls human destiny.

[24] In July 2018, it was announced that Mackie was cast in the role of Takeshi Kovacs for the second season of Netflix's science-fiction series, Altered Carbon.

[26] The following month, Disney confirmed a Marvel television series starring Mackie and Sebastian Stan, called The Falcon and the Winter Soldier, would be aired on their upcoming Disney+ streaming service, debuting on March 19, 2021.

[31] In January 2022, it was announced that Mackie will helm the drama film Spark, starring Saniyya Sidney, as his directorial debut project.

[32] In February 2022, he was set to lead action film Ending Things along with Priyanka Chopra Jonas, directed by Kevin Sullivan[33] and star in a live-action series adaptation of the game Twisted Metal at Peacock.

[34] In 2022, it was announced Mackie would be attached to a film based on the 1956 Sugar Bowl which features his brother's Alma mater Georgia Tech.

[42] In November 2013, Mackie was arrested for driving while intoxicated after he was initially stopped by police for having tinted windows, which are illegal in New York.