| 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 |
| Joan Cusack | Sheila Jackson |
| Emily Bergl | Sammi Slott |
| Regina King | Gail Johnson |
| Vanessa Bell Calloway | Carol Fisher |
| Nick Gehlfuss | Robbie Pratt |
| Maz Jobrani | Dr. Johnny |
| Morgan Lily | Bonnie |
| Isidora Goreshter | Svetlana |
| Ronnie Gene Blevins | Lewis |
| Nichole Sakura | Amanda
(as Nichole Bloom) |
| Adam Cagley | Ron Kuzner |
| Robert Cicchini | ER Doctor |
| Jim Hoffmaster | Kermit |
| Tobias Jelinek | Clay |
| Karen Maruyama | Dr. Ma |
| Michael Patrick McGill | Tommy |
| Ira Amyx | Ray |
| Eddie Arrazola | EMT #1
(as Eduardo Arrazola) |
| Sheldon Bailey | Kenyatta
(as Shel Bailey) |
| Barbara Allyne Bennet | Vicki |
| Chrisanne Eastwood | Cath |
| Selyna Warren | Ellen
(as Selyna Greenman) |
| Miguel Izaguirre | Paco |
| Dale Wade Davis | Gary |
| Emily Kosloski | Rudi |
| Kellen Michael | Chuck |
| Karthik Srinivasan | Shakhawat |
| Zach Steel | Jaybone |
| Abram Teunissen | Wolf |
| Malika Williams | Nurse Jarvin |
| Andrew Cole Abrams | Fireworks Boy
(uncredited) |
| Daria Badanina | Russian Hooker
(uncredited) |
| Mike Cochrane | Alibi Bar Regular
(uncredited) |
| Eric Lyons | Partier
(uncredited) |
| Brenden Sims | Liam Gallagher
(uncredited) |