George and Harold, and their doubles, Yesterday George and Yesterday Harold, have a good thing going. Two of them go to school, while the other two hide in the tree house and play video games all day- then they switch! But it turns out there's something rotten in the state of Ohio, and it's smellier than a pile of putrid gym socks. The boys' malicious gym teacher, Mr. Meaner, has created a method of mind control that transforms their fellow students into attentive, obedient, perfect children. Now the future of all humanity is in George and Harold and Yesterday George and Yesterday Harold's hands!
Continuing from where the last book left off, George and Harold and their doubles from the day before, Yesterday George and Yesterday Harold, are in big trouble once again. A few weeks from their last adventure, in which there were many loose ends, the city has been rebuilt and things are getting back to normal. Unfortunately, all their teachers including Mr. Krupp are still in jail, and they still have to take care of three bionic hamster/pterodactyls, Tony, Orlando, and Dawn. Meanwhile, in a different universe where a planet called Smart Earth orbits around the center star in Orion's Belt, everyone who lives their is highly intelligent due to the planet being made from a slightly radioactive element named Zygo-Gogozizzle 24 that can be mixed with mayonnaise and dill-pickle relish to create a clean-burning fuel source to light up an entire city and serve as a tasty salad dressing.
Even though Smart Earth is inhabited with geniuses, it has many similarities to our planet, having McDonald's, smartphones and the Huffington Post (which on Smart Earth are called Smart McDonald's, smart smartphones and the Huffington Post). One day, one of the smartest scientists at Smart Harvard University (a parody of Harvard) decided to do an experiment mixing Smart Diet Coke with Smart Pop Rocks and a third ingredient to the highly volatile concoction: Smart Mentos. The conduction of the experiment caused Smart Earth to explode, sending chunks of Zygo-Gogozizzle 24 throughout the galaxy, some landing in a pond on Badpun, a grape vineyard, on Pinot, and one piece that approached our own planet's atmosphere, in a small midwestern town of Piqua, Ohio. The tiny chunk crashed through the roof of the Piqua Valley Home for the Reality-Challenged, where George and Harold's elementary school teachers are being held.
Ms. Ribble thinks the piece of Zygo-Gogozizzle 24 is a meteorite, and the doctor warns them not to approach it. Unfortunately, Mr. Meaner, the gym teacher, doesn't listen and eats the chunk. He then becomes highly intelligent after the Zygo-Gogozizzle reaches his mind and supercharges all his brain cells. Mr. Meaner then speaks in a standard British accent and decides to leave the insipid infirmary, but the psychologists block the doors. Mr. Meaner immediately comes up with a plan to trick them, and tells them they should take his advice not to follow his advice. The two distracted doctors begin to argue if following his advice not to follow his advice is following his advice, Mr. Meaner slips out the open doors. Ms. Ribble notices her chance to escape, and she, along with all the other teachers, dart past the increasingly frustrated and confused doctors.
Outside, the teachers and staff follow Mr. Meaner up to the hilltop and watch in awe as he looks over the horizon, and announces that it occurred to him that all their recent problems were caused by wilful and disobedient children. He tells the teachers to follow his every command and to return to school and act normal. School restarts and it appears everything is back to normal, but meanwhile overnight Mr Meaner goes to an old, abandoned factory near Franz Pond and turns it into a makeshift laboratory. Inside, he creates Rid-O-Kid 2000™, a mind-control potion which turns even the most unruly child into a well-behaved child who follows the instructions of adults. He makes it from a base mixture of sodium thiopental containing liberal doses of butyric acid, tryptophan and Clamato juice and filters the solution through a pile of old, dirty gym socks.
The next day, Mr. Meaner arrives at school with two large spray tanks on his back and a metallic belt with buttons around his waist. After gym class, Mr. Meaner excuses all of the children except for Yesterday George and Yesterday Harold. He orders them into his office and locks the door after them. Inside his office, he sprays Yesterday George and Yesterday Harold with Rid-O-Kid 2000™ from the nozzles of his spray tanks. Yesterday George and Yesterday Harold go to their maths class and are well-behaved. Their maths teacher, Miss Calculator, is pleased with their behaviour. For the rest of the day, the other teachers notice how well the boys are behaving and after school finishes, they go to all their teachers and collect extra-credit homework.
Yesterday George and Yesterday Harold return to the tree house, where George and Harold are horrified at the amount of homework they have brought home. The four of them start completing their assignments, but George and Harold keep getting distracted. They work until bedtime. While Yesterday George and Yesterday Harold complete their half of the work, George and Harold barely do any of their half. Yesterday George suggests he and Yesterday Harold should go to school the following day while George and Harold stay up until 5:00am completing their work.
The following morning at school, Mr. Meaner also has robot arms and hands, having been building a giant mechanical ape suit named 'The Stinky-Kong 2000'. He sprays all of the children in his classes with Rid-O-Kid 2000™, giving them all 'Attention Superfluous Lethargy Syndrome (ASLS). Mr Krupp is delighted that Mr Meaner has transformed all the children. Ms Ribble asks if Rid-O-Kid 2000™ is dangerous and Mr Meaner explains to her that it only affects children and that adults are immune to it.
A few days later, George and Harold have caught colds due to staying up late to complete the homework Yesterday George and Yesterday Harold have brought home during the week. They decide to watch TV and come across a TV advert for Rid-O-Kid 2000™ featuring Mr. Meaner, which says:
"Are your kids annoying? Do they fight and whine and complain all the time? Do they refuse to eat anything but macaroni and cheese? Are they sucking the LIFE out of you? Well, Rid-O-Kid 2000™ is here to help. Our scientifically proven formula will transform even the most wilful child into an obedient, respectful and hardworking slave– er, I mean, angel. And Rid-O-Kid 2000™ has a full day's supply of Vitamin C, so you can feel GOOD about dosing your child with a narcotic that has never been tested for long term effects. So turn your brat into a brown-noser... with Rid-O-Kid 2000™. Rid-O-Kid 2000™ - the cure for childhood."
George and Harold dress up as an adult and go to school to find out what's going on. They see all the students acting as slaves for the teachers by doing their work for them, giving them massages, shaving their beards, plucking their eyebrows, giving them haircuts, filling our their tax forms and washing their cars. Harold exclaims that the teachers must have turned all the students into mindless slaves.
They disguised George and Harold then manipulate the children into doing the opposite of what they have been told to do, such as washing the windows wrong, filling their cars with cottage cheese and humiliating the teachers.
- This book is the the final book because at the end, it doesn't show a preview of Captain Underpants 13. The story doesn't end with "Oh, no! Here we go again!" either. And the most reasonable reason of all is that Mr. Krupp didn't turn back into you-know-who before the last chapter for some reason. Due to the series ending here, there are still some loose ends, with the main one being that back in book 10, Mr Krupp was still able to transform into Captain Underpants, but by the end of this book he cannot, this could be here to hint that a 13th book idea by Dav or fans is open. Another loose end is that Ms. Ribble is back to her original personality, as seen in Book 12, despite the effects of the 3D Hypno-Ring working differently on females.
- This book also reveals that Harold is, apparently, gay.
- In this book we learn that in the future George and his wife have kids named Meena and Nik (they are mixed-race, as their mother is white but their father is black) and Harold and his husband, Billy, have twins named Owen and Kei.
- The Dog Man graphic novel that George and Harold grab randomly from the bookshelf is titled "The Bark Knight Cometh".
- The back cover it is also shown that the book was commented on by New York Times and George's mom, though his mom's comment has a typo in it (The greatest graphic novel of the century).
- The back cover also shows a Flip-O-Rama notice, similar to all other Captain Underpants novels.
Breaking the fourth wall
- When Old George asks the two boys how come he and Old Harold have no memory of doing anything like this when they were kids, Harold says "I don't know." and George says "Probably bad writing."