| William H. Macy | Frank Gallagher |
| Emmy Rossum | Fiona Gallagher |
| Jeremy Allen White | Lip Gallagher |
| Ethan Cutkosky | Carl Gallagher |
| Shanola Hampton | Veronica Fisher |
| Steve Howey | Kevin Ball |
| Emma Kenney | Debbie Gallagher |
| Cameron Monaghan | Ian Gallagher |
| Noel Fisher | Mickey Milkovich |
| Emma Greenwell | Mandy Milkovich |
| Jake McDorman | Mike Pratt |
| Joan Cusack | Sheila Jackson |
| Emily Bergl | Sammi Slott |
| Harry Hamlin | Lloyd 'Ned' Lishman |
| Alex Borstein | Lou Deckner |
| Nick Gehlfuss | Robbie Pratt |
| Maile Flanagan | Connie |
| Isidora Goreshter | Svetlana |
| Raff Anoushian | Foreman |
| Sheldon Bailey | Kenyatta
(as Shel Bailey) |
| Eloy Casados | Roger Runningtree |
| Steven M. Gagnon | Bill Pratt |
| Lyn Alicia Henderson | Paramedic |
| Lynn Ann Leveridge | Nancy Pratt |
| Virginia Morris | Mrs. Bergdoll |
| Drew Rausch | Sgt. Benz |
| Montae Russell | Paramedic |
| Jonathan Schmock | Alan Kopchek |
| Americus Abesamis | Bouncer |
| Izabella Alvarez | Sarah |
| Brian Bogulski | Tennis Player |
| Jeffrey Cannata | Officer Goff |
| Michael Emery | Bruce |
| Carol Kiernan | Haleh |
| Michael Patrick McGill | Tommy |
| Cullen McCarthy | Ben
(as Cullen James McCarthy) |
| Jason Medwin | Sgt. Kelly |
| Kellen Michael | Chuck |
| Marlon Sanders | Officer Mirrione |
| Tai Urban | Gary |
| Daria Badanina | Russian Hooker
(uncredited) |
| Marcus Bradford | Hospital Patient
(uncredited) |
| James Chudnow | Trauma Victim
(uncredited) |
| Mike Cochrane | Alibi Bar Regular
(uncredited) |
| Natalia Rimareva | Doctor
(uncredited) |
| Brenden Sims | Liam Gallagher
(uncredited) |