| 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 |
| Richard Flood | Ford Kellogg |
| Christian Isaiah | Liam Gallagher |
| Katey Sagal | Dr. Ingrid Jones |
| Noel Fisher | Mickey Milkovich |
| Courteney Cox | Jen Wagner |
| Neal Bledsoe | Max Whitford |
| Andy Buckley | Randy |
| Jess Gabor | Kelly Keefe |
| Bob Saget | Father D'Amico |
| Abbie Cobb | Colette |
| Brian Scolaro | Baxter |
| Terrence Terrell | Antonio |
| Roman Arabia | Lester |
| Wes Armstrong | Gil |
| Raleigh Cain | Michelle Hill |
| Caroline Choi | Sister Frances |
| Amelia Engen | Lauren |
| Liz Jenkins | Bertha |
| Sarah Oh | Jessica |
| Wilson Ramirez | Barney
(as Wilson A. Ramirez Jr.) |
| Devon Reilly | Patty |
| Ian Sharkey | Fordie |
| Casper Smart | Johnny
(as Beau Casper Smart) |
| Rob Wilson | Fred |
| Robbie Dias | Hospital Patient Patron
(uncredited) |
| Candice Dylan | Bar-goer
(uncredited) |
| Kerri Mangold | Downtown pedestrian
(uncredited) |
| Mallory Mckenzie | Patsys Patron
(uncredited) |
| Paris Newton | Franny Gallagher
(uncredited) |
| Amber Pennington | Hotel Patron
(uncredited) |