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Clone High is set in a high school that is secretly being run as an elaborate military experiment orchestrated by a government office called the Secret Board of Shadowy Figures. The school is entirely populated by clones of famous historical figures, with the idea that they would later be used by the United States military who would harness their greatness in battle. The principal of the high school, Cinnamon J. Scudworth, has his own plans for the clones, however, and secretly undermines the wishes of the Board. Instead of using them as soldiers, Scudworth wants the clones to staff a clone-themed amusement park (dubbed "Cloney Island"). He is assisted by his robot/vice principal/dehumidifier Mr. Butlertron (an obvious parody of Mr. Belvedere) who calls everyone "Wesley".

The main protagonists of Clone High are the clones of Abraham Lincoln, Joan of Arc, and Mahatma Gandhi. Much of the plot of the show revolves around the attempts of Abe to woo the vain and promiscuous clone of Cleopatra. He is entirely ignorant of the fact that Joan of Arc is attracted to him. Meanwhile, John F. Kennedy's clone (referred to as "JFK"), a macho, narcissistic womanizer, is also attempting to win over Cleopatra and has a long-standing rivalry with Abe.

Many celebrities, including Tom Green, Andy Dick, Mandy Moore, John Stamos, Marilyn Manson, Michael J. Fox and Jack Black, make guest appearances on the show (sometimes as themselves). In addition, there are many amusing portrayals of famous historical figures, such as Julius Caesar, Catherine the Great, Genghis Khan, Vincent van Gogh, George Washington Carver, Walt Disney, Helen of Troy, Marie Curie (who is deformed, due to radiation damage to her DNA), and even Jesus Christ (who is portrayed as a latino named Jesús Cristo).

Much of the humor in the show comes from the large contrast between the personality of the clones and the actual values and legacy of the historical figures they are descended from. For instance, Gandhi is portrayed as a hyperactive jerk-with-a-heart-of-gold whose biggest dream is to be accepted by those around him, in contrast to his historical legacy of calm nonviolence. Abe Lincoln is similarly portrayed as weak and indecisive, completely lacking the resolve of the President whose DNA he shares. All of the clones are also given mis-matched foster parents who have little in common with them. Gandhi's parents are a stereotypical Jewish-American couple, while JFK is raised by a homosexual interracial couple; Joan's "foster grandpa" is an elderly blind musician similar to Ray Charles named Toots, who fills the stereotypical 'old wise man' role found in most teen shows, and who begins many of his declarative sentences with the words, "Now, I may be blind, but I can see..." followed by a wise-sounding observation that has little-to-nothing to do with anything.

The show is also a parody of "issue" episodes of high-school themed comedies; in fact, every episode opens with a voiceover parodying the "very special episodes" of TV shows. Episodes center on various social issues, including Gandhi being shunned by his school for having ADD (because of misinformation about the disorder), parodying shows which tackle AIDS awareness (it even included a special guest celebrity who tries to educate the students). Other episodes tackle drugs (smoking raisins), the environment, and underage drinking in a similarly ridiculous fashion. In a clear sign that it is parodying the high school genre, it even ends at prom — a stereotypical "high school show" ending. Even the prom is a joke however, as we learn it is only the Winter Prom.

The season finale is a cliffhanger episode, ending with the entire cast, aside from Scudworth, deep-frozen, and Joan in bed with JFK.

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