Set at a high school populated by clones of well-known historical figures, the series follows its central cast which includes adolescent depictions of Abe Lincoln, Joan of Arc, Gandhi, Cleopatra and JFK. Every episode is humorously introduced as a "very special episode" with narration provided by Will Forte. The show's design is heavily stylized and its animation style is limited, emphasizing humor and story over visuals. Many Scrubs alumni, such as Zach Braff, Donald Faison, Sarah Chalke, John C. McGinley, Neil Flynn, and Christa Miller, provided the voices of characters in Clone High.
The show centers on the clones of five famous historical figures: Abe Lincoln, Joan of Arc, Cleopatra, JFK, and Gandhi. The show is set in a high school in the fictional town of Exclamation, US, that is secretly being run as an elaborate military experiment.