- Tom Papa - Luff
- Rachel Izen - Nurse Braun
- Danny Hoch - Bunky Collier
- Grainger Hines - Captain August Robertson
- Michael Nathanson - Dr. Levi Zinberg
- Perry Yung - Ping Wu
- Reg Rogers - Dr. Bertram Chickering, Sr.
- Rachel Korine - Junia
- LaTonya Borsay - Mrs. Edwards
- Leon Addison Brown - Jesse Edwards
- John Hodgman - Doctor Entrusted with Eleanor
- Lucas Papaelias - Eldon Pouncey
- Frank Wood - Mr. Havershorn
- Kim Rideout - Cornelia's Maid
- Tom Lipinski - Phillip Showalter
- Happy Anderson - Jimmy
- Michael Berresse - Parke Davis Rep.
- Suzanne Savoy - Victoria Robertson
- Alfred Cole - Prize Fighter
- Molly Price - Effie Barrow
- Zuzanna Szadkowski - Nurse Pell
- David Wilson Barnes - Dr. Hackett
- Charles Aitken - Cornelia's Brother
- Johanna Day - Eunice Showalter
- Matt Frewer - Dr. J.M. Christiansen
- David Fierro - Inspector Jacob Speight
- Melissa Errico - Catherine Christiansen
- Karl Bury - Mr. Corker
- Kate Easton - Mrs. Warren
- Cait Cortelyou - Nurse Monk
- Christopher Dalbey - Bleier Driver
- Aija Terauda - Mrs. Krawetz
- Monty Stuart - Pete
- Zenon Zeleniuch - Slum Landlord
- Emily Bergl - Mrs. Hemming
- Rob Morgan - Diggs Man
- Victoria Leigh - Cora Hemming
- Andy Murray - Clarence Mulkeen
- Bridget Barkan - Nora
- David Neal Levin - Mr. Olynyk
- Ryan Homchick - Orderly Schleif
- Rob Michael Hugel - Mr. Gatchell
- Dean Neistat - McCarthy
- Erika Rolfsrud - Edwards' Patient's Mother
- Pernell Walker - Ida Harris
- Jennifer Ferrin - Abigail Alford
- Pei Pei Lin - Chinese Prostitute
- Pei Pei Lin - Chinese Prostitue
- Ylfa Edelstein - Nurse Baker
- Antwayn Hopper - Woodson
- Adam Mucci - Dietz
- Craig muMs Grant - Hernia Patient
- Brian Tyree Henry - Larkin
- Phillip Chorba - Quinn
- Clarke Thorell - McTeague
- Tom Treadwell - Mr. Edison
- Maja Wampuszyc - Mrs. Zygmund
- Jon Patrick Walker - Doctor at Orphanage
- Helen Coxe - Miss Carhart
- Brian Kerwin - Corky
- Peter Maloney - Barber / Doc
- Emily Kinney - Nurse Daisy Ryan
- Makenzie Leigh - Amy O'Connor
- Erin Wilhelmi - Lottie
- Athan Sporek - Paulo (Street Urchin)
- Henry Gagliardi - Krawetz Kid (uncredited)
- Maya Kazan - Eleanor Gallinger
- Sawyer Barth - The Whispering Kid
- Dominique Fishback - Black Girl
- Danya LaBelle - Mrs. Lefkowitz
- Arielle Goldman - Genevieve Everidge
- Ying Ying Li - Lin-Lin
- Jonah Coppolelli - Paper Boy, Working Class Boy
- Melanie Brook - Frances
- Jack Amiel
- Michael Begler
- Gregory Jacobs
- Carmen Cuba
- Cliff Martinez
Clive Owen interpreta a Dr. John Thackery en la serie.
André Holland hace el papel de Dr. Algernon Edwards.
Jeremy Bobb interpreta a Herman Barrow en la serie.
Juliet Rylance hace el papel de Cornelia Robertson.
Eve Hewson interpreta a Lucy Elkins en la serie.
Michael Angarano hace el papel de Dr. Bertram “Bertie" Chickering, Jr..
Cara Seymour hace el papel de Sister Harriet.
Eric Johnson interpreta a Dr. Everett Gallinger en la serie.
Chris Sullivan hace el papel de Tom Cleary.
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