Rick, in a drunken state, takes his grandson, Morty, for a ride in his flying car and rambles on about how he plans to use a neutrino bomb to wipe out all life on Earth. Rick lands the vehicle on Morty's demand and passes out. The bomb activates by itself and seems to be left unchecked, but ultimately it is shown that life on Earth remains intact. After having breakfast with their family, Rick takes Morty to another dimension to collect seeds of "Mega Trees", which Morty is forced to hide in his own rectum to get past intergalactic customs. However, Rick and Morty's cover is blown and they escape while engaging in a shootout with alien insects. Ultimately, the seeds briefly cause Morty to be highly intelligent, despite the fact that he missed a semester of school because he's been in adventures with Rick. This causes his parents to believe he is fine with his education, but this wastes the seeds, so Rick informs Morty that they need to go back and get more, while their aftereffects leave Morty writhing on the floor.
On Christmas, Rick sends Morty inside the body of a homeless man to save his life (a parody of Fantastic Voyage). Inside the man's body is a microscopic enclosure called Anatomy Park (a parody of Jurassic Park), which houses various deadly diseases that escape their enclosures. Back at the family home, Jerry's parents visit, and the family attempts to bond without electronic devices.
Post-credit scene: Rick contacts Annie and her other new associates inside his new patient's body and as they talk about his "Pirates of the Pancreas" ride (much to Rick's dislike, since he is sensitive about his ride because it's his idea). Rick hangs up on them only to proceed with a rant and insults, also revealing Summer's boyfriend Ethan as the new Anatomy Park host.
Morty is interested in going to the dance at his school with his classmate Jessica, so he asks Rick for a love potion. However, because Jessica has the flu, the potion becomes airborne and goes haywire, causing not only her but the whole population of Earth to fall for Morty save for blood relatives. Rick attempts to fix up an antidote, but he fails twice, ultimately causing all humans affected by the love potion to turn into mutated monsters called "Cronenbergs" (a reference to famous director of body horror films David Cronenberg). Meanwhile, Jerry visits Beth in her workplace because he is concerned about her fidelity, and they find Summer later. Rick and Morty then migrate to another dimension where their duplicates died soon after successfully curing all of Earth, thus allowing Rick and Morty to assume their roles.
Post-credit scene: Jerry, Beth and Summer are happy to stay together as the only normal human family in their post-apocalyptic mutated world, glad that Rick and Morty are gone. Two Cronenberg versions of Rick and Morty come from the "Cronenberg world" to live there as well, because their home was inhabited by Cronenbergs all along, which were accidentally transformed into normal people.