Fry has a flashback of himself and his Dad going ice fishing in 1988, as the Planet Express crew go ice fishing. They don't have much luck, and after a whole day of no bites, they go back to the headquarters with only a baby fish - and a common cold. Professor Farnsworth explains that the common cold has been extinct for more than 500 years. Soon after, a quarantine shield is put on top of the Planet Express building, and everyone (except Bender) catches the cold. Although Bender is needed to help the others during their illness, he escapes with germs on his hands, caught from Zoidberg accidentally sneezing on him. He then congratulates the quarantine crew, shaking their hands, and giving them the germs. The quarantine crew soon catches the cold, and there is a new outbreak.
After 99% of the city gets the cold, a bigger quarantine shield is put on the city, which is then lifted physically out of the ground. Using tractor beams, the island of Manhattan is carried towards the Sun, towed by the starship Nimbus. The professor says that developing a vaccine is possible, but it requires the unmutated 20th century cold virus which only Fry has. As Fry is attached to a machine, preparing to be sliced gruesomely into a thin paste (to obtain a sample of the virus), he has a flashback of a high school science contest that he had entered. His entry, (A common cold virus contained in Fry's pet hamster) lost to a boy in Fry's class who also used the common cold (preserved and cultured immaculately) as his experiment, which was subsequently sent into space.
In the future, Fry remembers this and stops himself from being pureed. Fry recalls that the experiment was shot into space, carried on a satellite which was sent to one of the frozen moons of Saturn as a garbage dump. They initially cannot escape their confinement since the barrier is too strong to yield to the weapons of the crew. They devise a plan where they trick the Nimbus into attacking them. As the Nimbus shoots at the Planet Express crew, they swerve and are able to exit through the substantially sized hole now produced in the quarantine shield, thanks to the power of the Nimbus' weapons. The crew finds the experiment on Saturn's moon under the ice, perfectly preserved. Since the virus culture was professionally prepared and the experiment sealed untouched under the ice for over one thousand years, the Professor is able to engineer a vaccine. Farnsworth administers vaccinations to a very long line of New New Yorkers, waiting for their turn, including Ogden Wernstrom.
At the end of the episode, Fry has one final flashback showing him and his father in the ice fishing shack after he gets pulled out of the ice by his father. Fry and his father talk, and during the conversation his father shows one of the first, if not the only, signs of love towards Fry in the series. Fry's father offers him a beer, which Fry accepts. His father admits he has been tough in raising his son, but tells him that it was only because he wanted Fry to grow up to be strong, and able to face whatever adversity he is presented with. He speculates that Fry may one day experience adversity so great, it would have been inconceivable to him before, alluding to his eventual experiences in the future. Fry's father ends the episode by placing a warm jacket on the shivering boy, along with the words "I don't want you to get frozen." This is a very touching and sad comment, as it can be interpreted as Fry literally being frozen a few years later, losing his entire family in the process.
Leela joins the rest of the crew in beating-up Fry, after the news encourages them to do so.
When the Professor attempts to strangle Fry with a scarf, Leela does not intervene.
When the Professor is about to grind Fry into a paste, in order to obtain the original, un-mutated cold virus, Leela tries to stop him. Fry, showing some maturity, is willing to sacrifice himself in order to save Leela, and by extension everyone else, from possible death by the Common Cold.
Owing to his part in saving Manhatten Island, Leela gives Fry a heartfelt compliment.