| 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 |
| Frankie Faison | Acting Commissioner Ervin H. Burrell |
| Lawrence Gilliard Jr. | D'Angelo Barksdale
(as Larry Gilliard Jr.) |
| Wood Harris | Avon Barksdale |
| 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
(credit only) |
| Seth Gilliam | Sgt. Ellis Carver |
| Domenick Lombardozzi | Det. Thomas 'Herc' Hauk
(credit only) |
| Jim True-Frost | Det. Roland 'Prez' Pryzbylewski |
| James Ransone | Chester 'Ziggy' Sobotka |
| Pablo Schreiber | Nick Sobotka |
| Michael Hyatt | Brianna Barksdale |
| Bill Raymond | The Greek |
| Al Brown | Maj. Stanislaus Valchek |
| Hassan Johnson | Roland 'Wee-Bey' Brice |
| Delaney Williams | Sgt. Jay Landsman |
| Maria Broom | Marla Daniels |
| Luray Cooper | Nathaniel 'Nat' Coxson |
| Erik Dellums | Dr. Randall Frazier
(as Erik Todd Dellums) |
| Charley Scalies | Thomas 'Horseface' Pakusa |
| Chris Ashworth | Sergei 'Serge' Malatov |
| Gerard Ender | Sam |
| Jeffrey Fugitt | Claude Diggins |
| Brook Yeaton | Michael 'White Mike' McArdle |
| Nat Benchley | Det. Augustus Polk
(uncredited) |
| Antonio D. Charity | CO Dwight Tilghman
(uncredited) |
| Jeffrey Coleman | Coast Guard Officer
(uncredited) |
| Robert F. Colesberry | Det. Ray Cole
(uncredited) |
| Paul D'Elia | Harbor Patrol Cop
(uncredited) |
| Kelvin Davis | La La
(uncredited) |
| Leslie Elliard | Off. Kevin Reynolds
(uncredited) |
| Jeffrey Pratt Gordon | John 'Johnny Fifty' Spamanto
(uncredited) |
| Bill Heneghan | MPA Officer
(uncredited) |
| Bus Howard | Vernon 'Ott' Motley
(uncredited) |
| David L. Marston | Long Shoreman
(uncredited) |
| David Ian McKendry | Inmate
(uncredited) |
| Jeremy Nichols | First Mate
(uncredited) |
| Jill Redding | Delores
(uncredited) |
| Jennifer Rouse | Prostitute
(uncredited) |
| Schuster Vance | Walt Stokes
(uncredited) |
| E. Parker Webb | Stevedore
(uncredited) |
| Michael Willis | Andy Krawczyk
(uncredited) |