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| Series Regulars | |||
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| Andre Royo | Andre Royo as Reginald "Bubbles" Cousins | Clarke Peters | Clarke Peters as Det. Lester Freamon |
| Domenick Lombardozzi | Domenick Lombardozzi as Thomas "Herc" Hauk | Frankie Faison | Frankie Faison as Ervin H. Burrell |
| John Doman | John Doman as William A. Rawls | Lance Reddick | Lance Reddick as Lt. Cedric Daniels |
| Larry Gilliard Jr. | Larry Gilliard Jr. as D'Angelo Barksdale | Michael Kostroff | Michael Kostroff as Maurice "Maury" Levy |
| Robert Wisdom | Robert Wisdom as Howard "Bunny" Colvin | Sonja Sohn | Sonja Sohn as Det. Shakima "Kima" Greggs |
| Wendell Pierce | Wendell Pierce as Det. William "Bunk" Moreland | | |
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| Recurring & Guests | |||
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| Callie Thorne | Callie Thorne as Elena McNulty | Jim True-Frost | Jim True-Frost as Det. Roland "Prez" Pryzbylewski |
| Method Man | Method Man as Melvin "Cheese" Wagstaff | Michael B. Jordan | Michael B. Jordan as Wallace |
| Paul Ben-Victor | Paul Ben-Victor as Spiros "Vondas" Vondopoulos | Tristan Wilds | Tristan Wilds as Michael Lee |