| Dominic West | Det. James 'Jimmy' McNulty |
| John Doman | Maj. William A. Rawls |
| Idris Elba | Russell 'Stringer' Bell |
| Frankie Faison | Dep. Comm. for Operations Ervin H. Burrell
(as Frankie R. Faison) |
| Lawrence Gilliard Jr. | D'Angelo Barksdale
(as Larry Gilliard Jr.) |
| Wood Harris | Avon Barksdale |
| Deirdre Lovejoy | Asst. State's Atty. Rhonda Pearlman |
| Wendell Pierce | Det. William 'Bunk' Moreland |
| Lance Reddick | Lt. Cedric Daniels |
| Andre Royo | Reginald 'Bubbles' Cousins |
| Sonja Sohn | Det. Shakima 'Kima' Greggs |
| Peter Gerety | Judge Daniel Phelan |
| Seth Gilliam | Det. Ellis Carver |
| Domenick Lombardozzi | Det. Thomas 'Herc' Hauk |
| Leo Fitzpatrick | Johnny Weeks |
| J.D. Williams | Preston 'Bodie' Broadus
(as JD Williams) |
| Clarke Peters | Det. Lester Freamon |
| Jim True-Frost | Det. Roland 'Prez' Pryzbylewski |
| Hassan Johnson | Roland 'Wee-Bey' Brice |
| Michael Kenneth Williams | Omar Little
(as Michael K. Williams) |
| Tray Chaney | Malik 'Poot' Carr |
| Wendy Grantham | Shardene Innes |
| Michael B. Jordan | Wallace
(credit only) |
| Delaney Williams | Sgt. Jay Landsman |
| Maria Broom | Marla Daniels |
| Michael Kostroff | Maurice 'Maury' Levy |
| Melanie Nicholls-King | Cheryl |
| Michael Salconi | Det. Michael 'Sanny' Santangelo |
| Jarvis W. George | 'Ronnie Mo' Watkins
(as Jarvis George) |
| Michael Hyatt | Brianna Barksdale |
| Curtis Montez | Sterling |
| Edward T. Norris | Det. Edward Norris
(as Edward Norris) |
| Benay Berger | FBI Supervisor Amanda Reese |
| Doug Olear | FBI Spec. Agent Terrance 'Fitz' Fitzhugh |
| Susan Rome | Asst. State's Atty. Ilene Nathan |
| Stephen F. Schmidt | Brice's attorney |
| Perry Blackmon | Perry
(uncredited) |
| Pete Burris | Federal judge
(uncredited) |
| Robert F. Colesberry | Det. Ray Cole
(uncredited) |
| Terrence Currier | Roy Brown
(uncredited) |
| Richard DeAngelis | Maj. Raymond Foerster
(uncredited) |
| Larry Derr | Onion
(uncredited) |
| De'Rodd Hearns | Herbert De'Rodd 'Puddin' Johnson
(uncredited) |
| Mike Lavoie | Rookie Cop
(uncredited) |
| Toni Lewis | FBI Agent
(uncredited) |
| Kirk Penberthy | FBI Spec. Agent Arnold D. Paulette
(uncredited) |
| Eric Ryan | Sean McNulty
(uncredited) |
| Aaron J. Savage | Court Suspect
(uncredited) |
| William Shipman | Philadelphia Detective
(uncredited) |
| Dave Trovato | Maj. Walter Cantrell
(uncredited) |
| Gary Wheeler | Attorney
(uncredited) |