The comic's name is a pun on the 1954 book The War Whoop of the Wily Iroquois.
The comic starts at a nuclear waste plant (It has lots of waste apparently as the book describes). A truck arrives to gather the waste and take it all to a dump. However one of the barrels of nuclear waste fall off the truck and it rolls down into a cotton field. It leaks into the soil and makes the cotton grow really fast. Soon, for Tim's Cotton come and pick the cotton. They complain that it's big and heavy. It then gets taken to Bub's Underwear Factory. As the cotton is used to make underwear, one of the workers notices that the underwear is glowing.
Months later, Melvin's mom buys him a pair of glow-in-the-dark underwear. He wears it at his house and his mother says he's the coolest kid ever. While Melvin sleeps, he starts to grow until he makes holes in the house. He gets up in the morning and walks to school saying "Duh, I'm grumpy!". A police officer says to the chief that a giant rampaging nerd is destroying the town. The chief says to call the army and stuff. So, the army and stuff comes.
A big war begins. The Wily Wonder Nerd grabs a tank and throws it. It then lands on a gym teacher at a nearby school. After the principal receives the news (he was initially worried about who Wonder Nerd squished until the children reveal the gym teacher was squished and he becomes relieved that it wasn't somebody important), he and the kids call out to Captain Underpants, who comes in and he flies around Melvin's underpants and reads that the underpants are supposed not to be in water, otherwise it will shrink. Melvin captures Captain Underpants who begs not to dunk him in the lake. Melvin takes him to the lake and gets into the water to drown the Captain. Suddenly, Melvin's underpants shrink. Then, he is capable of blowing up. So Captain Underpants calls a bird and it pops Melvin by puncturing a hole in him with its beak, releasing air from Melvin's body.
Everyone yells out hooray for him except Melvin. Captain Underpants then takes Melvin to the jail for "dumb stupid nerds". He then flies with one last "Tra-La-Laa!" as the comic ends. There is also a moral at the end saying that you should always wear pre-shrunk underwear.