| Dominic West | Off. James 'Jimmy' McNulty |
| Chris Bauer | Frank Sobotka |
| Paul Ben-Victor | Spiros 'Vondas' Vondopoulos |
| John Doman | Col. William A. Rawls
(credit only) |
| 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
(credit only) |
| 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
(credit only) |
| Domenick Lombardozzi | Det. Thomas 'Herc' Hauk
(credit only) |
| Jim True-Frost | Det. Roland 'Prez' Pryzbylewski |
| James Ransone | Chester 'Ziggy' Sobotka |
| Pablo Schreiber | Nick Sobotka |
| Kristin Proctor | Aimee |
| Callie Thorne | Elena McNulty |
| Michael Kenneth Williams | Omar Little
(as Michael K. Williams) |
| Al Brown | Maj. Stanislaus Valchek |
| Richard Burton | Sean 'Shamrock' McGinty |
| S. Robert Morgan | Butchie |
| Charley Scalies | Thomas 'Horseface' Pakusa |
| Delaney Williams | Sgt. Jay Landsman |
| Shamyl Brown | Donette |
| Luray Cooper | Nathaniel 'Nat' Coxson |
| Michael Mack | Special Agent Marcus Lemmel |
| Kevin Murray | Special Agent Kleary |
| Ernest Waddell | Dante |
| Kelli R. Brown | Kimmy |
| Edwina Findley | Tosha Mitchell |
| Keith Flippen | Bruce DiBiago |
| Jon Garcia | Ringo |
| Tel Monks | Father Jerome Lewandowski |
| James E. Ash | Uniform Officer
(uncredited) |
| Nat Benchley | Det. Augustus Polk
(uncredited) |
| Eric Buarque | Long Shoreman
(uncredited) |
| Antonio D. Charity | CO Dwight Tilghman
(uncredited) |
| Enrique Chicas | Courthouse Police Officer
(uncredited) |
| Antonio Cordova | Michael McNulty
(uncredited) |
| Erik Dellums | Dr. Randall Frazier
(uncredited) |
| R. Andrew Doan | Extra
(uncredited) |
| Jeffrey Pratt Gordon | John 'Johnny Fifty' Spamanto
(uncredited) |
| David L. Marston | Long Shoreman
(uncredited) |
| Melanie Nicholls-King | Cheryl
(uncredited) |
| Jonathan Pope | Sergeant
(uncredited) |
| Jill Redding | Delores
(uncredited) |
| Eric G. Ryan | Sean McNulty
(uncredited) |
| Jonathan Watkins | Tony, City Councilman
(uncredited) |
| Isiah Whitlock Jr. | State Sen. R. Clayton 'Clay' Davis
(uncredited) |