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Partially filmed in a closed hospital (North Hollywood Medical Center in the San Fernando Valley in California) which is also the same hospital that Scrubs (2001) filmed in.

Michael Cera's character's name (Sal Viscuso) is a reference to actor Sal Viscuso who voiced the iconic PA announcer on M*A*S*H (1972)

In 2011, Corddry stated that the cast and creative team of Childrens Hospital were working on doing a movie together, separate from Childrens Hospital, with a different story and characters. In 2017, Corddry announced that a spin-off series of Childrens Hospital was in development: a global mystery/thriller structured around a season-long serial narrative. The new series is to feature a number of the original cast, and share the comedic tone of Childrens Hospital, but will be unlike Childrens in most other respects.

Though Comedy Central made a competing offer, the show was picked up by Adult Swim after Corddry decided the comedy style was not suited for the half-hour format Comedy Central wanted. Adult Swim offered half-hour or fifteen-minute time slots, and Corddry chose the latter. The original season one webisodes began airing on Adult Swim on July 11, 2010, in groups of two with a new faux-commercial in between the groupings of two webisodes. The channel then debuted the newly produced season two episodes which began airing on August 22, 2010.

Rob Coddry (Dr. Blake) put less blood on his scrubs starting from season 3 due to complaints for putting too much in the previous seasons