The series had run in its entirety in Canada on Teletoon before premiering in the United States on MTV. The last five episodes were never broadcast in the United States. The Theme Song is written by Liam Lynch and performed by alternative rock band The Abandoned Pools who also provided much of the series' background music.
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, that have been created and raised, with the intent of having their various strengths and abilities harnessed by the military. The principal of the high school, Cinnamon J. Scudworth, has his own plans for the clones, and secretly tries to undermine the wishes of the Board (Scudworth wants to use the clones to create a clone-themed amusement park, dubbed "Cloney Island", his intentions with the clones being decidedly less evil than those of the Board). He is assisted by his robot assistant/vice principal/dehumidifier Mr. Butlertron (a parody of Mr. Belvedere), who is programmed to call everyone "Wesley" (a reference to one of the main characters in Mr. Belvedere).
The main protagonists of Clone High are the clones of Abraham Lincoln, Jeanne D'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 VII of Egypt, while being oblivious to 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 portrayals of clones of famous historical figures, such as Julius Caesar, Catherine the Great, Genghis Khan, Vincent Van Gogh , George Washington Carver, Helen of Troy, Gautama Buddha, Juan Ponce de León (who appears as a cross between himself and Arthur Fonzarelli and is known as "Poncey"), Maria Sklodowska-Curie (who is deformed, due to radiation damage to her DNA), and even Jesus Christ (who is portrayed as a latino named Jesús Cristo always shown in shop class doing carpentry).
The season, and as of 2003, series finale is a cliffhanger episode, ending with the entire cast, aside from Principal Scudworth and Mr.Butlertron, deep-frozen.
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 gay interracial couple; Joan's "foster grandpa" is an elderly blind musician similar to Ray Charles named Toots, who fills the stereotypical wise old man role (and the magical negro 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 also includes humor based on the historical figures themselves. For example, the diner the clones frequent is called The Grassy Knoll, a nod to the JFK assassination conspiracy theory about a second shooter, dubbed "The Man on the Grassy Knoll". Other references seen are the flag at The Grassy Knoll being permanently at half mast and the car on the roof of the diner containing the original JFK's body leaning over the edge. There are pictures of assassinations hanging on the walls of the restaurant, such as the famous Currier and Ives print of the Lincoln assassination (though this version is in color and considerably more graphic than the original print). The genetic ancestors of all of the main five clones died of similarly irregular causes: three assassinations, one execution, and one suicide. Other historical figure-based humor includes offhand coincidental remarks to other students, such as Abe mentioning that the clone of Napoleon I of France is so annoying because of "some kind of complex", or Gandhi telling a rude Catherine II of Russoc to "get off her high horse".
The show is also a parody of "issue" episodes of high-school themed comedies; in fact, almost every episode opens with a voice-over 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 drug use (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.
There was a running gag that creators Phil Lord and Christopher Miller wanted to include in the show "where Clone High – being an exaggeration of typical high schools in teen dramas – would have many proms throughout the year". Planned proms included "An Early Winter Prom, a Late Winter/Early Spring Prom, a Mid-Semester Prom, a Post-Prom Clean Up Prom, etc". Due to the show's early cancellation, the only references to this joke are the Homecoming Prom in "Homecoming: A Shot in D'Arc", and the winter prom in episode 13, "Changes: The Big Prom: The Sex Romp: The Season Finale".
During the process of writing an episode, the writers would all get together to pitch jokes. Often, a writer would pitch an extension onto a joke, then another writer would pitch another extension, and so on, until it became what the writers called a wacky stack, a joke so bloated and over-written it was no longer funny.
- Abe Lincoln: A naïve yet nice guy, forever wrestling with the legacy of his clonefather, Abraham Lincoln. He is in love with Cleopatra. Voice by Will Forte.
- Joan of Arc: A cynical, regretful, and angst-ridden goth clone of Joan of Arc with a crush on her best friend, Abe. Although she does not seem to be an obvious goth, she called herself one during a confession to Jesús Cristo in the third episode. Voice by Nicole Sullivan.
- Gandhi: Buckling under the pressure of being a clone of Mohandas Gandhi, he has become a non-stop party machine instead. Voice by Michael McDonald. His portrayal as a party animal enraged many in India, including prominent members of India's parliament.
- Cleopatra: A sharp, sultry, seductive, cruel and manipulative clone of Cleopatra VII of Egypt. She has a big ego and sees herself as a queen. Voice by Christa Miller.
- JFK: The obnoxious, womanizing school jock, who believes he is doing a good job of living up to John F. Kennedy, whom he believes to have been "A macho, womanizing stud who conquered the MOON!" He has an even bigger ego than Cleo. Voice by Christopher Miller.
- Principal Cinnamon J. Scudworth, Ph.D.: A deluded, self-aggrandizing megalomaniac who always wears rubber dish-gloves and has an annual psychological breakdown after which he attempts to kill John Stamos. He is voiced bt Phil Lord.
- Mr. Butlertron: A robot who is programmed with a highly sensitive compassion protocol (a parody of Mr. Belvedere). Also known as Mr. B. He calls everyone "Wesley", a reference to the youngest son on Mr. Belvedere, Wesley Owens. He is voiced by Christopher Miller.
- Mr. Sheepman: A kindly history teacher at Clone High, and the first mostly human clone with a little sheep DNA mixed into his genetic composition (a parody of Dolly the Sheep). His mannerisms are a parody of Don Knotts. He is voiced by Andy Dick.
- Secret Board of Shadowy Figures: A secretive government organization who employs Principal Scudworth and is sponsored by Puma AG.
- Marie Curie: A girl who has a crush on Gandhi. Being cloned from Madame Curie's DNA, there was a lot of toxic chemicals in the cloning process, causing her to be horribly disfigured and mutated.
- Van Gogh: A depressed, suicidal emo kid who thinks he's a failure at life. Has a talent for painting. Van Gogh gets bullied by the other kids at the school, and he injects his emotional trauma into his art.
- Julius Caesar: A linguistic talking, fancy guy. JFK's friend.
- George Washington Carver: A nerdy guy, who does scientific experiments on peanuts. He is usually very stoic and serious, especially when people like Gandhi come into the picture and annoy him.
- Peany: A genetically modified, peanut, which has been brought to life and befriended by George Washington Carver.
- Nostradamus: A guy with the ability to predict the future.
- Catherine the Great: A popular girl, who talks with a valley girl accent. Cleo's friend.
- Genghis Khan: A special needs kid, who's bigger and stronger than most other students of the school.
- Jesús Cristo: A highly religious Mexican man, who works in woodshop. His moral compass is controlled entirely by his faith in God, and of course, his clonefather The Original Jesus Christ of Nazareth.
- Adolf Hitler: A politically correct, equal rights activist.
- Thomas Edison: A condescending know-it-all, and the school nerd. Talks in a nasally voice, and constantly snorts and inhales deeply.
- Brontë sisters: Three cheerleader girls, who adore JFK and follow him around, everywhere.
- Elvis Twins: Clones of Elvis Presley and his stillborn twin brother. The former is a slick and smooth ladies man, while the latter is an overweight drug addict, just asking for death to take him away.
- Abe's Foster Mom: The woman, who serves as the foster father of Abe Lincoln.
- Abe's Foster Dad: The man, who serves as the foster father of Abe Lincoln.
- Toots: The foster father of Joan of Arc. He's a blind, black guy, who's disability really gets in the way of everything. Despite his stupidity and tendency to screw things up with his lack of eyesight, Joan looks up to him and loves him dearly.
- Gandhi's Foster Mom: A stereotypical Jewish woman, who fosters for Gandhi.
- Gandhi's Foster Dad: A stereotypical Jewish man, who fosters for Gandhi.
- Cleo's Foster Mom: The drunken, slutty foster mother of Cleo, who supports the way she acts. Cleo's Foster Mom is jealous of how young and beautiful her daughter is, now that she is old and past her prime.
- Wally and Carl: The gay foster dads of JFK, whose homosexuality and pansy behavior greatly contrasts, JFK's womanizing, chauvinistic, straight guy attitude.
- Original Abraham Lincoln: The original Abraham Lincoln, of whom Abe was cloned from. Abe looks up to his clonefather for wisdom and advice, wishing to one day live up to the man he was. The spirit of Abraham usually appears, in places like Abe's dreams, and five dollar bills, to lead him in the right direction.
- Helen of Troy: The clone of Helen of Troy.
- Napoleon Bonaparte: A guy who runs a restaurant.
- Paul Revere: The school gossip.
- Buddy Holly: A music lover.
- Martin Luther King, Jr.: A black rights activist.
- Moses: A Jewish rights activist.
- Karen Carpenter: An anorexic anorexia activist.
- Susan B. Anthony: A feminist.
- Eva Perón: A highly religious, wacko lady.
- Rock Hudson: A closeted homosexual, who's had many girlfriends.
- Confucius: The clone of Confucius.
- Ponce de León: The deceased clone of Joan Ponce De Leon. He was JFK's best friend and was portrayed a main cast member in "Litter Kills: Litterally", to make his overhyped death seem more dramatic.