| Clive Owen | Dr. John W. Thackery |
| André Holland | Dr. Algernon Edwards |
| Jeremy Bobb | Herman Barrow |
| Juliet Rylance | Cornelia Robertson |
| Eve Hewson | Nurse Lucy Elkins |
| Michael Angarano | Dr. Bertie Chickering Jr. |
| Chris Sullivan | Tom Cleary |
| Cara Seymour | Sister Harriet |
| Eric Johnson | Dr. Everett Gallinger |
| Maya Kazan | Eleanor Gallinger |
| Grainger Hines | Captain August Robertson |
| Charles Aitken | Henry Robertson |
| Rachel Korine | Junia |
| Michael Nathanson | Dr. Levi Zinberg |
| Jarlath Conroy | The Hypnotist |
| Colman Domingo | Dr. Russell Daniels |
| Chris Elliott | Port Authority Officer |
| Linda Emond | Anne Chickering |
| Jennifer Ferrin | Abigail Alford |
| Arielle Goldman | Genevieve Everidge |
| John Hodgman | Dr. Henry Cotton |
| Ntare Guma Mbaho Mwine | D.W. Garrison Carr |
| Reg Rogers | Dr. Bertram Chickering, Sr. |
| Frederick Weller | Mr. Brockhurst
(as Fred Weller) |
| Annabelle Attanasio | Dorothy Walcott |
| Rebekah Brockman | Nettie |
| Melanie Brook | Frances |
| Jay Carrado | Man in Zoya and Nika's Room |
| Chelsea Clark | Vera |
| Roberto De Felice | Gino Petrizzi |
| Rocco Di Gregorio | Tenement Man |
| Rachel Farrar | The Knick Receptionist
(as Rachel E. Farrar) |
| Andy Grotelueschen | Hypnotized Man |
| Miranda Gruss | Zoya |
| Rebecca Gruss | Nika |
| Aedin Moloney | Sister Mary Michael |
| Lucas Papaelias | Eldon Pouncey |
| Jonathan Randell Silver | Mt. Sinai Orderly
(as Jonathan Randall Silver) |
| Zuzanna Szadkowski | Nurse Pell |
| Ginger A. Taylor | Sonya Smyslov
(as Ginger Taylor) |
| Norman Aaronson | Immigrant
(uncredited) |
| Jonathan Ercolino | Circus Goer
(uncredited) |
| Vin Hamilton | Surgical Theater Reporter
(uncredited) |
| Teddy Kalin | Immigrant
(uncredited) |
| Ernesto Nodal | Immigrant
(uncredited) |
| And Palladino | Gallery Doctor
(uncredited) |
| Jamie Theurich | Soup Vendor
(uncredited) |