The book continues where the previous book left off; the narrator wants to have a complete child-oriented Captain Underpants book.
We land on a planet called “Smart Earth”, whose inhabitants are intelligent because of Zygo-Gogozizzle 24, a radioactive element which was created by mixing mayonnaise with pickle relish. The planet is similar to our Earth but with everything labeled "smart". One scientist was mixing "smart" Diet Coke with "smart" Pop Rocks, with "smart" Mentos as the third ingredient. However, this causes the planet to explode. Chunks fall on other planets, including Earth, with one landing at Piqua Valley Home for the Reality-Challenged, where George and Harold's teachers are held for punishment.
Mr. Meaner eats a chunk of the meteorite, giving him superpowers and speaking in an English accent. The other teachers follow him as he takes control of the children of Piqua, sending them back to school and overruling the city. Yesterday George and Yesterday Harold visit Mr. Meaner’s office, which they have been before. Mr. Meaner sprays them, turning them into slaves who act like robots. The other teachers, as well as Mr. Krupp, are amazed at their behavior, but George and Harold, however, are not.
The next day, Mr. Meaner is now turning other students into slaves as well with his Stinky Kong 2000. Meanwhile, George and Harold are now getting sicker because of their excessive homework, as they see a television commercial for the “Rid-O-Kid 2000”. To see what's going on, they disguise themselves as an adult. The children are following the teachers’ every command, but George and Harold make them do silly things, such as cleaning up all wrong, make all the teachers look silly, put cottage cheese in their cars, and other opposites of what the teachers want.
The teachers had enough of their shenanigans, so they called in Mr. Meaner to fix things and see what’s going on. He finds out that the children are doing the opposite of what the teachers command them to do. Enraged, he got out his Stinky Kong 2000.
George and Harold find that their parents know that they’ve changed. Feeling heartbroken, they went into Melvin’s house to find his Robo-Squid, then travels back in time to find their older selves and their families (we also find out that Harold is gay). Later, the younger versions once read a random chapter of Dog Man: The Bark Knight Cometh.
The older and younger versions of George and Harold travel back in time to find Mr. Krupp. The older George and Harold tried to snap their fingers, but as he was sweating, he could not turn into Captain Underpants, and Mr. Meaner beats them up anyway. Once they snapped their fingers, they turn him into Captain Underpants, defeating Sir Stinks-A-Lot and sending him into prison.
After eating an egg salad sandwich with pickle relish, Sir Stinks-A-Lot turns into a blob (because the egg salad contains mayonnaise and he added pickle relish; this would create Zygo-Gogozizzle 24). He then causes havoc downtown. Captain Underpants returns to fight him back, but when Old George and Old Harold are captured, Captain Underpants couldn’t save them, as Sir Stinks-A-Lot turns him back into Mr. Krupp with water, therefore falling down (he was still unharmed because of his super powers). He runs off screaming as Old George and Harold telepathically calls for Tony, Orlando, and Dawn, who are completely awake. They find Mentos, Diet Coke, and Pop Rocks, making Sir Stinks-A-Lot explode. Luckily, the three hamsterdactyls and Old George and Old Harold are unharmed, as well as Mr. Meaner.
Things were back to the way they were, and as young George and Harold return their older counterparts to their own time, they find that Mr. Krupp didn’t turn into Captain Underpants at the snap of a finger, because Mr. Meaner erased Captain Underpants from existence. Yesterday George and Yesterday Harold also find out that Tony, Orlando, and Dawn are gone.
George and Harold were back to their tree house. Harold feels that he and George should make another Captain Underpants comic book, but George decides that he and Harold should do a comic book featuring Dog Man. The book and series end here, and unlike all those other Captain Underpants adventures, George and Harold did NOT shout their titular cries of "OH, NO!" and "Here we go again!". However, George and Harold's comic book The Adventures of Dog Man: World's Greatest Cop (later renamed just Dog Man) would be another Captain Underpants spin-off book, released on August 30, 2016.
This is a random chapter. Dog Man "betrays" the cops by assaulting them, then he reveals that he's actually Petey the cat. He tries to slice them up with his sword, but above, Dog Man – as his superhero alter ego, "The Bark Knight" – falls toward Petey and breaks his sword with his bone numb-chucks. The two engage in a fight, and while this is happening, Petey shoots hand rockets at Dog Man, revealing he's actually Mecha-Petey (a robot version of Petey). He assaults Dog Man, then Milly – a cop – kicks Mecha-Petey in the face, removing it and revealing he's actually Porkbelly, an angelfish.George Beard and Harold Hutchins - Two mischievous best friends who are fourth graders at Jerome Horwitz Elementary School.
Yesterday George and Yesterday Harold - George and Harold's doubles.
Old George and Old Harold - George and Harold's older counterparts.
Mr. Krupp - George and Harold's mean principal.
Captain Underpants - Mr. Krupp's superhero counterpart.
Mr. Meaner / Sir Stinks-A-Lot - George and Harold's mean gym teacher who is the main antagonist of this book.
Tony, Orlando, and Dawn - Three super hamsterdactyls and the offspring of Sulu and Crackers.
Ms. Ribble - George and Harold's English teacher.
Miss Anthrope - The secretary of Jerome Horwitz Elementary School.
Miss Calculator - George and Harold's math teacher.
Mr. Rected - The school guidance counselor.
Mr. Rustworthy - The school's music teacher.
Miss Labler - The school psychologist.
Ms. Guided - The school staff member.
Miss Fitt - The school cafeteria woman.
Ms. Dayken - The kindergarten teacher.
Warden Gordon Bordon Schmorden - The jailer of Piqua State Penitentiary.
Mary - George's Caucasian future wife.
Billy - Harold's future husband.
Meena and Nik, George's future children. They are mixed race, as their mother is white and their father is black.
Owen and Kei, Harold's future children.
In October 2015, the book received controversy due to a reference to Harold being gay. Some elementary schools have banned the book for this reason.