| William H. Macy | Frank Gallagher |
| Emmy Rossum | Fiona Gallagher |
| Justin Chatwin | Jimmy |
| Ethan Cutkosky | Carl Gallagher |
| Shanola Hampton | Veronica Fisher |
| Steve Howey | Kevin Ball |
| Emma Kenney | Debbie Gallagher |
| Cameron Monaghan | Ian Gallagher |
| Noel Fisher | Mickey Milkovich |
| Jeremy Allen White | Lip Gallagher |
| Emma Greenwell | Mandy Milkovich |
| Zach McGowan | Jody Silverman |
| Joan Cusack | Sheila Jackson |
| Harry Hamlin | Lloyd 'Ned' Lishman |
| Eric Edelstein | Bobby Mallison |
| Madison Rothschild | Molly
(as Madison Moellers) |
| Galadriel Stineman | Wendy |
| Charles Henry Wyson | Hanley |
| Julie Ariola | Patty |
| J.J. Boone | Jenica |
| Sally Ann Brooks | Lucy
(as Sally Brooks) |
| Ellen Gerstein | Aunt Rande |
| Roberta Valderrama | Princess |
| Sharon Benson | Dirty Joan Baez |
| Michael Blum | Male Counselor |
| Miles Brown | Ashish |
| Juliocesar Chavez | Chubby Kid |
| Claudine Claudio | Coupon Woman |
| Brittany Giles | Bald Cancer Girl |
| Cooper Gillespie | Anne |
| Michael Tuba Heatherton | Moppy the Clown
(as Michael Heatherton) |
| Tonja Kahlens | Lois |
| Michael Patrick McGill | Tommy |
| Kevin Mukherji | Pawn Shop Owner |
| Kerry O'Malley | Kate |
| Janet Song | Korean Woman |
| Isabella Cuda | Cancer Girl
(uncredited) |
| Eric John Dugan | Postal Carrier
(uncredited) |
| Brenden Sims | Liam Gallagher
(uncredited) |