- 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 hace el papel de Dr. John Thackery.
André Holland interpreta a Dr. Algernon Edwards en la serie.
Jeremy Bobb interpreta a Herman Barrow en la serie.
Juliet Rylance interpreta a Cornelia Robertson en la serie.
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 hace el papel de Dr. Everett Gallinger.
Chris Sullivan hace el papel de Tom Cleary.
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