At the Planet Express building, Professor Farnsworth announces some "good news" to the Planet Express crew that their delivery to a planet has been canceled due to the planet being quickly and through unknown means destroyed, the only good news being that they paid in advance. Hearing the news, Nibbler runs off downtown, chased by Leela. Leela looks for Nibbler, tempting him with a ham. Going down an alley Leela is suddenly chased by gigantic flying brains. She finds Nibbler on the other side of a fence pulling a little space ship out of a makeshift hanger. She begs Nibbler to help her, but Nibbler only answers with a sad face and flies off, only to change his mind.
To Leela's surprise Nibbler comes back and rescues her, Leela being crammed into his ship. Nibbler telepathically talks to her explaining that he is a super intelligent being from a race of aliens that he been watching over the universe and that he is taking her to his home planet. Meanwhile back on Earth, Fry shows up for work and mysteriously finds everyone has become dumb, including Bender freaking out when he finds that his "skin" is all cold and clanky, and asks, "Am I a robot?" when Fry explains that all the things he finds weird is because he's a robot.
On Nibbler's home world Leela meets the rest of Nibblonians, who explain that they have been fighting the "Brains" since the beginning of the universe. They also explain that all the recently destroyed planets, including Tweenis 12, were each attacked by the Brains. They explain to Leela that the Brains have a need to know everything and that they hate all other life because the thoughts of other beings hurt them. So to keep other beings from thinking the brains telepathically target the delta brainwave which allows thought in all beings. This causes the attacked being to become stupid. The Niblonians also tell Leela that there is only one person who can stop the brains, and that person is Fry as he lacks the Delta Brain Wave which all beings including humans, robots, and plants have, but Fry for some reason doesn’t, instead gathering an assortment of other brain waves into a working one.
Back on Earth, Fry tries to get everyone to stop acting so stupid, first yelling it through the wrong end of a megaphone, then he tries to re-educate his co-workers through his own school class. Back on Nibbler's planet they think of a plan to stop the brains, their fleet in orbit of Earth the Nibblonians plan to send Leela down to earth to deliver their message to Fry to find and defeat the Brain's leader. Leela unfortunately can't be trusted to remember the message as when back on Earth she will be as stupid as everyone else. So they simply write the message on a note and tape it to her chest.
Leela is sent down in a small ship and crash lands in the Planet express building, struggling due her stupidity. She tries to give Fry the letter but her believes it simply to be a tissue and throws it away. Leela tries to explain that the Brains are what’s making everyone dumb; Fry doesn’t believe her until he sees two floating in the window. Taking Leela seriously Fry decides to track down the Brains' leader; realizing that a brain is like a giant nerd, Fry realizes that the Brain leader is hiding at the New New York Library.
Once there, Fry and Leela confront the Big Brain, who has assimilated all of the library's information thanks to the Dewey decimal system. Fry tries to attack it with a book but fails. Fry tries to think of a way to hurt it and realizes that thinking hurts it. Unable to take it the Brain mentally takes their minds and its own into the books on the table including Moby Dick, Tom Sawyer and Pride and Prejudice. Fry manages to free himself by getting out of range from the brain in real life, only to be crushed under a book case in a failed attempt to kill the Brain. This reality is then revealed to be a false one; Leela and the brain are still trapped in the book world. Having been through all the other books, they are now in one that Fry is writing. To top it off Fry writes that the big Brain leaves for no reason (which Fry spelled as raisin), defeated, the Brains fall to the ground while the Niblonian soldiers eat them. With the Brains' "Delta Brain wave attack" gone and Niblonians having disappeared, everything is back to normal; no one except Fry remembers what happened.