| Dominic West | Off. James 'Jimmy' McNulty |
| Chris Bauer | Frank Sobotka |
| Paul Ben-Victor | Spiros 'Vondas' Vondopoulos |
| John Doman | Col. William A. Rawls |
| Idris Elba | Russell 'Stringer' Bell
(credit only) |
| Wood Harris | Avon Barksdale
(credit only) |
| Deirdre Lovejoy | Asst. State's Atty. Rhonda Pearlman |
| Clarke Peters | Det. Lester Freamon |
| Wendell Pierce | Det. William 'Bunk' Moreland |
| Lance Reddick | Lt. Cedric Daniels |
| Amy Ryan | Off. Beatrice 'Beadie' Russell |
| Sonja Sohn | Det. Shakima 'Kima' Greggs |
| Seth Gilliam | Sgt. Ellis Carver |
| Domenick Lombardozzi | Det. Thomas 'Herc' Hauk |
| Jim True-Frost | Det. Roland 'Prez' Pryzbylewski |
| James Ransone | Chester 'Ziggy' Sobotka |
| Pablo Schreiber | Nick Sobotka |
| Robert Hogan | Louis Sobotka |
| Bill Raymond | The Greek |
| J.D. Williams | Preston 'Bodie' Broadus
(as JD Williams) |
| Chris Ashworth | Sergei 'Serge' Malatov |
| Teddy Cañez | George 'Double G' Glekas
(as Ted Feldman) |
| Jeffrey Fugitt | Claude Diggins |
| Lance Irwin | Maui |
| Charley Scalies | Thomas 'Horseface' Pakusa |
| Kelvin Davis | La La |
| Bus Howard | Vernon 'Ott' Motley |
| Richard Pelzman | Little Big Roy |
| Jeffrey Pratt Gordon | John 'Johnny Fifty' Spamanto |
| J. Valenteen Gregg | Chess |
| Tray Chaney | Malik 'Poot' Carr
(uncredited) |
| Luray Cooper | Nathaniel 'Nat' Coxson
(uncredited) |
| Billy Finnigan | Bernard
(uncredited) |
| Daniel Garrett | Gus the Bartender
(uncredited) |
| De'Rodd Hearns | Herbert De'Rodd 'Puddin' Johnson
(uncredited) |
| Bill Heneghan | MPA Officer
(uncredited) |
| Kevin Jiggetts | Frommers
(uncredited) |
| Jill Redding | Delores
(uncredited) |