- Kevin Fonteyne - Derrick Wells
- Jonathan Silverman - Dr. John Lieberman
- Tara Summers - Allison McDaniels
- Mason Cook - Quinn McDaniels
- Eyal Podell - Mark Ridgeway
- Anthony Giangrande - Dr. Thomas Ottobrini
- Matt Crabtree - Gordon Willis
- Cara Pifko - Beth Hostetler
- Nija Okoro - Aisha Ali
- Kevin Shinick - Levi Hostetler
- Sonya Eddy - Joanne Whitman
- Sharon Muthu - Dr. Sharika Kumar
- Blake Robbins - Dr. David Martin
- Laura Richardson - Nurse Veronica Woolward
- Robb Reesman - Surgeon Leigh Durrell
- Patrick Quinlan - EMT
- Betsy Baker - Mrs. Sutcliff
- Lou Volpe - Mr. Sutcliff
- Rachael Drummond - Mrs. Wilson
- Jonny Lee - James
- Cozi Zuehlsdorff - Trisha Miller
- Valerie Dillman - Yvonne Miller
- Bradley White - Owen Miller
- Del Hunter-White - Mrs. Jasper
- Elena Campbell-Martinez - Mariah Gonzales
- Ewan Chung - Doctor Wong
- Ewan Chung - Wong
- Eden Riegel - Sandy Slade
- Rusty Burns - Gladys
- Jason Gray-Stanford - Atty. Scott Henderson
- Burl Moseley - Technician
- Adam Rose - Joe Newton
- Gian Franco Tordi - Gianni
- Anthony Heald - Mitch Tompkins
- Valerie Mahaffey - Fran Horowitz
- Raphael Sbarge - Mr. Cooper
- Arabella Field - Marilyn Cooper Kupcheck
- Dale Raoul - Eloise Fernwood
- Rakefet Abergel - Carla
- Jill E. Alexander - Anesthesiologist
- Mike Grief - Floyd Fernwood
- Cat Hammons - Psych Ward Nurse
- Adrian Quinonez - Paramedic
- Kaelyn Raye Lustig - Emma Cooper
- Lou Saliba - Male Patient
- Devon Bostick - Benjamin Decada
- Samantha Hanratty - Abra Rivers
- Meeghan Holaway - Priscilla Rivers
- Dean Cudworth - Lionel Rivers
- Alexandra Bokyun Chun - Mrs. Park
- Zylan Brooks - ER Nurse
- Ryan McCartan - Daniel
- Jeff Clarke - Frank Valente
- Hal Holbrook - Dr. Arvin Wayne
- Annika Marks - Tory Britton
- Matthew Yang King - Tsung Mai
- Rob Brownstein - Transplant Surgeon
- Denzel Whitaker - Nick Villanueva
- Charlie Bodin - Glenn Kubiak
- Sage Mears - Morgan Britton
- Jeremy Denzlinger - Paramedic
- Wendy Haines - Scrub Nurse
- Sarah Hudson - Circulating Nurse
- Reiley McClendon - Jacob Gold
- Holley Fain - Kara Bishop
- Wilmer Calderon - Mike Garrett
- Derek Mio - Alex Kimura
- Whitney Avalon - Lori Newton
- Dave Engfer - Dr. Mac Ryan
- Ioan Gruffudd - Dr. Stewart Delany
- Lukas Behnken - Keith Harriman
- Rhonda Aldrich - Ms. Harriman
- Tim Martin Gleason - Dan Ford
- Yvonne Caro Caro - Elena Cabrera
- Marcos De Silvas - Fernando Cabrera
- Maya Goodwin - Anesthesiologist
- Johnny Kostrey - Paramedic
- Nicole Pettis - Paramedic
- Jon Schmidt - Paramedic
- A.J. Tannen - Anesthesiologist
- Megan Gallagher - Ms. Wells
- Bonnie Bailey-Reed - Ellen Coolidge
- Akeem Mair - Family Visitor
- Akeem Mair - Chef
- William Charlton - George Coolidge
- Sumalee Montano - Lynne Iverson
- John Burke - News Anchor
- Mercedes Ruehl - Judge Beverly Natheson
- Anna Moon - Respiratory Therapist
- Kenneth Mitchell - Asher Knox
- Spencer Daniels - Gregory Malloy
- Cleo Berry - Darryl Fisher
- Denise Dowse - Mrs. Fisher
- Harry S. Murphy - Judge
- Bashir Gavriel - Paramedic Roth
- Carmella Riley - Nurse Gladys Doise
- Bill D'Elia
Alexandra Bokyun Chun interpreta a Mrs. Park en la serie.
Mercedes Ruehl interpreta a Judge Beverly Natheson en la serie.
Ving Rhames interpreta a Dr. Jorge Villanueva en la serie.
Jamie Bamber interpreta a Dr. Tyler Wilson en la serie.
Jennifer Finnigan interpreta a Dr. Tina Ridgeway en la serie.
Bill Irwin interpreta a Dr. Buck Tierney en la serie.
Keong Sim hace el papel de Dr. Sung Park.
Sarayu Blue hace el papel de Dr. Sydney Napur.
Emily Swallow hace el papel de Dr. Michelle Robidaux.
Alfred Molina hace el papel de Dr. Harding Hooten.
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