| 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 |
| Emily Bergl | Sammi Slott |
| Dermot Mulroney | Sean Pierce |
| Steve Kazee | Gus Pfender |
| Jenica Bergere | Lisa |
| Nichole Sakura | Amanda
(as Nichole Bloom) |
| Isidora Goreshter | Svetlana |
| Bojana Novakovic | Bianca Samson |
| Michael B. Silver | Lorenzo |
| Luca Oriel | Derek |
| Axle Whitehead | Davis |
| Susan Chuang | Dr. Kathy Beard |
| Demetrius Grosse | Eddie Murphy |
| Jim Hoffmaster | Kermit |
| Michael Patrick McGill | Tommy |
| Kellen Michael | Chuckie Slott |
| Stephen Rider | G-Dogg |
| J. Michael Trautmann | Iggy Milkovich |
| Erik Aude | Drug Cop
(as Erik Anthony Audé) |
| Greg Bryan | Police Officer |
| Missy Hairston | Gina |
| Steve Hasley | Dr. Thompson |
| Shanna Malcolm | Pharmacist |
| Dora Pereli | Sherry |
| Ted Sima | Police Officer #2 |
| Brenden Sims | Liam Gallagher |
| Shelby Steel | Muff |
| Christopher Stills | Chris
(as Chris Stills) |
| Virginia Watson | Desk Cop |
| Celine Zapata | Alice
(as Celine Whelan) |
| Mike Cochrane | Alibi Bar Regular
(uncredited) |
| Shaun Daley | Alibi Bar Patron
(uncredited) |
| Mark Mammone | Orderly
(uncredited) |
| Brett McCabe | College Alcohol Enthusiast Holding Beer Bongs
(uncredited) |