The movie begins with a voiceover by Will Stronghold (Michael Angarano) explaining that in his world, there are a large number of superheroes. And the greatest heroes of all are the super-strong Commander (Kurt Russell) and the high-flying Jetstream (Kelly Preston). While the rest of the world only knows these two as heroes, Will explains that they are his parents, Steve & Josie Stronghold, who also operate one of the most successful real-estate chains in the country. Will is about to begin high school and will be attending his parents' alma mater-a school just for super-powered individuals. There is just one problem, Will explains... He has no powers.
Steve & Josie are planning their schedule when Will's friend Layla stops by to go to the bus with Will. Josie offers Layla some breakfast (bacon & eggs) but Layla turns it down since she is a vegan (her mother can speak with animals, and "they don't like being eaten.")
Steve goes up and finds Will in front of a weight bench (Will is faking having super-strength to not disappoint his father). Steve gives Will a pep talk about entering high school and expresses his hope that one day Will can be around to save the world.
Suddenly, Steve & Josie receive a call on their special red cell phones. The Commander and Jetstream are needed! The parents say goodbye to Will and go down to the Secret Sactum, their base of operations to suit up for action. They travel downtown where a giant Robot is attacking the city. Jetstream drops Commander onto the Robot, smashing it. The crowd cheers as Commander rips out the Robot's eye for a trophy.
Will & Layla arrive at the bus stop. When the bus arrives, Ron Wilson (Kevin Heffernan) the driver mocks Will for being a freshman until he learns that Will is the son of Commander & Jetstream. Will meets up with his friend Zach (Nicholas Braun) who is bragging about having finally gained his powers. Layla meets two other students- Ethan (Dee Jay Daniels) and Magenta (Kelly Vitz)
Ron Wilson takes the bus through a construction zone and ends up driving it right off a bridge! He calmly flips some switches as wings & rocket engines are engaged as the bus flies up to their new school- SKY HIGH. Ron explains that the school is kept up by anti-gravity propulsion and remains in constant motion to avoid detection.
The freshman get off the bus and are immediately confronted by two bullies- Lash (Jake Sandvig) who has stretching abilities and Speed (Will Harris) who has supersonic movement. The bullies' attempt to con money out of the freshman is stopped by Gwen Grayson (Mary Elizabeth Winstead) the student body president. She gives the freshman a lecture about Sky High, but Will is completely captivated by her and does not hear a word.
As the freshman enter the gym, a sparkling silver comet shoots past them. It lands at the podium and spins around to reveal Principal Powers (Lynda Carter). She wishes the students good luck at Sky High.
Next, Coach Boomer (Bruce Campbell) arrives in the gym to begin Power Placement. The class members are asked to step up and demonstrate their powers, and Boom will assign them to a class- Hero or Sidekick (also called "Hero Support," which Magenta refers to as "Loser-Class.") Zach eagerly steps up and shows off his power- he can glow in the dark. Boomer is not impressed and knocks Zach off the stand with a supersonic boom, classifying Zach as a sidekick.
The remaining freshman go through placement at a steady pace. Along the way, Ethan (whose power lets him melt into a puddle) and Magenta (who can turn into a guinea pig) are both assigned to Sidekick class. Layla, who does not approve of this system, refuses to participate- and is thus made Sidekick by default. The bell rings and Coach Boomer orders a break for lunch, deciding that he will start things off with Will when they get back.
At lunch, Will notices a strange boy in leather who appears to be staring at them. Magenta recognizes him as Warren Peace, (Steven Strait), child of a superhero mother and a supervillian father. Apparently, Will's father captured Warren's father and sent him to jail on "quadruple life sentences." Will is miserable- it's his first day and he already has an archenemy!
Back in the gym, Coach Boomer attempts to test Will's powers by dropping a car on him and throwing him across the room. Will finally confesses that he has no powers. Boomer pronounces Will "Sidekick" with such firmness that it shatters a dozen windows."
Will gets examined by the school nurse (Cloris Leachman), who cannot explain why he is powerless. She says that he might eventually get one or both of his parents powers, but there are rare cases where children of superheroes never develop powers. Apparently the last known case of a powerless child is none other than Ron Wilson, the bus driver.
Will comes home and his father wants to have a talk with him. Steve brings Will into the Secret Sactum, swearing Will to secrecy and making Will promise not to bring anyone else in. The Sanctum is loaded with trophies from The Commander's battle (He places the Robot Eye from that morning on a pedestal), including a weapon called the Pacifier from a villian called Royal Pain-the first enemy that Commander and Jetstream defeated together. Steve then reveals that he has placed Will's name on an empty pedestal in the hope that Will can someday be a great hero. Will chickens out and cannot tell his father about being a Sidekick.
Meanwhile, the Robot Eye glows (unnoticed by Steve & Will). The Sanctum is being watched by two mysterious entities.
Layla stops by to talk to Will using her powers (she can control plant growth). Layla encourages Will to tell his father the truth, but he still refuses.
The next day, Hero Support class begins as Will & his friends meet their teacher, All-American Boy (Dave Foley). "Mr. Boy" reveals that he once worked with the Commander, and seems hurt when Will does not know about him.
The power goes out in the building, and Zach immediately takes the opportunity to show off his glowing powers. Mr. Medula (Kevin McDonald), the science professor with an oversized cranium arrives and explains that there was a minor "misfire" in the Mad Science Lab.
The week goes on with Will & his friends receiving instructions from Mr. Boy and Mr. Medula. Ethan becomes a favorite target of bullies Speed & Lash, frequently becoming on the receiving end of "swirlies." One night, Will & the other sidekicks are at Will's house studying when The Commander returns home. Will cannot hide the truth anymore and confesses the truth: he is a Sidekick, and he is powerless. The Commander is at a loss for words.
Steve and Josie speak later. Josie is disappointed too, but there is nothing they can do "short of dropping [Will] in a vat of toxic waste." Steve resolves that Will can always make a legitimate career out of real estate rather than being a hero, and his disappointment does not defer his love for his son.
Next day at lunch in Sky High cafeteria, Lash uses his stretch powers to trip Will. Will's lunch tray accidentally lands on Warren Peace, who is furious. Warren reveals his power (to project fire from his arms) and attacks Will. Will cowers under the lunch table, unable to fight back. When Warren threatens the other Sidekicks, Will reaches up and lifts the entire table that Warren is standing on! Will (and everyone else) suddenly realize that he has gained super-strength. Warren, angry about being knocked down, attacks again. Will punches him with such force that Warren crashes into the teacher's lounge. Undaunted, Warren gets back up and attacks again. Layla tosses Will a fire extinguisher, and Will rips the top off and extinguishes Warren's fire.
Principal Powers throws Will and Warren in a detention room. Warren is eager to keep fighting, but cannot ignite his flames. Principal Powers explains that the detention rooms neutralize super-abilities. Will attempts to resolve the matter peacefully, but Warren wants nothing of the sort.
That night, Will returns home thrilled about his good fortune. Josie is not amused, since her son destroyed a good portion of the cafeteria. Steve takes Will to the Sactum for a discussion, but upon arrival he firmly embraces Will, delighted that his son has super-strength. Will hugs back to demonstrate just how strong he is. Steve gives Will an X-Box as a reward for developing superpowers.
The mysterious figures continue to watch from the Robot Eye.
Back in class, Will's friends are happy about the way he stood up for them. Mr. Boy comes in and explains that Will has now been upgraded to the Hero class. Will arrives at Mr. Medula's science class and is partnered with Gwen Grayson and instructed to build a Freeze Ray. Will is completely lost in his new class, so Gwen uses her powers (she is a technopath; with the ability to control various forms of technology) to help him.
At lunch, Will meets with Gwen to catch up on his new Hero-Class requirements. He also meets her friend Penny (Malika Khadijah) a girl with the ability to duplicate herself. Penny and some of the other Heroes dismiss the sidekicks as losers. Will, feeling bad, offers to take Layla to the Paper Lantern (her favorite Chinese restaurant) later that night. She happily accepts.
Will sees Speed & Lash shoving Ethan and Zach into lockers. Ethan and Zach think Will can stop them for good, and makes a bet: If Will can out-perform Speed & Lash in Gym Class, they will not harm the sidekicks for the rest of the year. If Will fails, they will stick Ethan's head in a toilet every day.
In Gym Class, Coach Boomer explains the exercise "Save the Citizen." A team of 2 students must overpower 2 "Villains" and reclaim an endangered "person" (actually just a dummy) before it falls into a spiked pit. Speed & Lash are the undefeated champions. They will act as the Villains and choose Stronghold & Peace for the Heroes. At first, Will & Warren are losing badly because they cannot work together. Will manages to tie up Lash (literally) but Warren is trapped by Speed's circular dash. Warren collapses under the strain, since Speed's vortex is sucking away the oxygen needed for his fire-powers. Warren encourages Will to forget him and rescue the citizen, but Will ignores the citizen and takes out Speed. With only seconds left, Will uses a "fastball special" to throw Warren over the spike pit, rescuing the citizen!
The Commander is thrilled to hear about his son's accomplishment, since no freshman has ever won "Save the Citizen" before. Gwen shows up at Will's house to help him with his science homework. She gets along fabulously with Will's parents. They look over Steve & Josie's old yearbook from Sky High, and spot a photo of a girl named Sue Tenny who looks suspiciously like Gwen. Gwen asks The Commander and Jetstream to come to Homecoming as guests of honor to receive the award for "Heroes of the Year."
Layla is at the Paper Lantern, waiting for Will. She meets Warren, who has a job at the restaurant. Warren theorizes that Layla is secretly in love with Will. Layla confirms this, but is afraid that Will is in love with Gwen. At the same time, Will walks Gwen home, and she invites him to the Homecoming dance as her date. Will is so happy that he ends up knocking over a lamppost.
Next morning, Will apologizes to Layla for missing the dinner at Paper Lantern. Layla is happy until Will explains that he is going to homecoming with Gwen. Layla, devastated, asks Warren to take her to homecoming. Warren does not like the prospect of it, but when he decides that taking Layla will spite Will, he happily agrees.
Later that week, Will & Gwen decide to meet up with Homecoming committee to discuss the dance. The entire Hero class ends up at Will's house to throw a party. Gwen asks Will if there is a quiet place where they can talk in private. Will takes her to the one place in the house that is quiet- the Sanctum. Gwen kisses Will while an unseen figure comes in and swipes the Pacifier weapon.
Layla shows up at the party, and Gwen lies to her by saying that Will is sickened by her feelings for him. Layla, heartbroken, walks out. Will, seeing his friend cry, angrily breaks up with Gwen and tells everyone to leave. They ignore him, but at that moment the Commander and Jetstream return home. Everyone immediately rushes out.
Will explains that he didn't actually plan the party, and will not be going with his parents to Homecoming. Steve encourages Will to come to the dance, because he wants to introduce "The Stronghold Three," the greatest superhero family in the world.
Will goes to the Paper Lantern in an attempt to talk things over with Layla. Warren meets him and explains that he is only going with Layla to make Will jealous. Will doubts that Layla or any of the other Sidekicks will speak to him again.
That night, Commander & Jetstream leave for homecoming while Will stays in the Sactum. Will looks through his father's old yearbook and sees the girl who looks suspiciouly like Gwen holding a device that looks like the Pacifier! Upon seeing that the real Pacifier is gone, he contacts Ron Wilson for an emergency transport to Sky High.
At the Homecoming dance, Gwen meets Commander & Jetstream once again and reveals her true self- Gwen is the supervillain Royal Pain! Royal Pain uses the Pacifier on Commander, and it turns him into an infant. Several other members are hit by the Pacifier ray while Speed, Lash and Penny seal all the exits. Warren, Layla and the Sidekicks manage to escape in an air vent. Zach uses his powers to show them the right way out, when they suddenly meet up with Will.
Will confirms that Gwen is apparently the daughter of Royal Pain, and apologizes to his friends for being such a jerk since his promotion to Hero-class. Layla kisses Will as a means of forgiveness. Warren tells Will to go after Gwen while they take care of the henchmen.
Ethan runs away, managing to trap Lash's head in a toilet in the process. Warren fights with Speed but cannot hit the dashing bully. Speed runs right in front of Ethan, who promptly melts. Speed slips up on the puddle and Warren blasts Speed into a wall.
Will confronts Gwen, who is taking the infant heroes away to start her own academy of super-villains by re-raising the heroes from scratch. Gwen also confirmes that in truth, she IS Sue Tenny. The original Pacifier weapon backfired on her, so she waited to grow up again and exact revenge. Will is disgusted- he's been in love with "an old lady!"
Royal Pain smashes Will through the wall of the gym. Meanwhile, Penny is still fighting Layla. Layla is finally fed up with the battle and uses her powers to summon a massive growth of vines and ensnare Penny and all her duplicates. Penny reveals that Royal Pain is tampering with the schools' anti-gravity device and that in 10 minutes, Sky High will fall.
Zach, Ethan, Layla and Magenta look at the blueprints for Sky High. They see a small opening to the anti-gravity room that none of them can fit through- except Magenta in her guinea-pig form.
Will & Royal Pain are still fighting when she lands a devastating punch, sending Will flying out of a window and off Sky High. Seconds later, Will returns to the same spot, revealing his SECOND power: Flight!!!
Royal Pain is loading a bus with the infant heroes when Ron Wilson notices and shuts down the bus, preventing their escape.
Magenta reaches the anti-gravity device just as it shuts down, and she begins to chew through a wire. Will flies out and attempts to stop the school from falling. Magenta chomps through the wire seconds before Sky High slams into a residential neighborhood.
With the school re-stabilized, Will & his friends wonder how to proceed. Mr. Medula (still possessing his fabulous intelligence despite being an infant) decides to re-program the Pacifier.
As the heroes are gradually restored to normal, Will apologizes for letting Gwen into the Sanctum. The Commander and Jetstream decide that the "Hero of the Year" award should rightfully go to Will & his friends (including Ron Wilson) for stopping Royal Pain. With everyone returned to normal, they resume the Homecoming dance.
Will gives a voiceover during the end credits, explaining "my girlfriend became my archenemy, my archenemy became my best friend, and my best friend became my girlfriend. But hey- that's high school!"