Whitlock's manager Brian Liebman wrote on Instagram: "It is with tremendous sadness that I share the passing of my dear friend and client Isiah Whitlock Jr.
"If you knew him - you loved him. A brilliant actor and even better person. May his memory forever be a blessing. Our hearts are so broken. He will be very, very missed."
Liebman told Deadline that the actor died peacefully following a short illness.
Whitlock was born in South Bend, Indiana, and a guest appearance on CBS's Cagney & Lacey in 1987 was among his first screen roles.
His work in TV also included the Law & Order franchise, with episodes each on Special Victims Unit and Criminal Intent.
He is best known for playing corrupt state senator R Clayton "Clay" Davis on the acclaimed TV series The Wire, while he also had memorable roles on Veep and Your Honor.
His last TV role was as the Chief of Police on Netflix's White House murder mystery The Residence.
In movies, he was known for his collaborations with Oscar-winning director Lee, appearing in six of his films: 25th Hour (2002), She Hate Me (2004), Red Hook Summer (2012), Chi-Raq (2015), BlacKkKlansman (2018) and Da 5 Bloods (2020).
Lee took to Instagram to pay tribute to Whitlock, writing: "Today I Learned Of The Passing Of My Dear Beloved Brother ISIAH WHITLOCK. GOD BLESS."
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