A month after the universe was ripped open in Futurama: Bender's Big Score, people decide to go on with their lives. Amy and Kif get married. Fry starts dating a girl named Colleen, but breaks up with her when he discovers she has many more boyfriends.
At a scientific conference, Professor Farnsworth proposes an expedition to investigate the anomaly after beating his rival, Wernstrom, in a game of Deathball (a gigantic version of Labyrinth). When Bender explores the anomaly, his touch causes it to emit a shock wave that sends him and the ship flying. Farnsworth and Wernstrom discover that only living beings can pass through the anomaly; electrical objects such as robots are either repelled or destroyed. The two plan to initiate another expedition but are rejected in favor of a military assault on the anomaly led by Zapp Brannigan.
Meanwhile, both Fry and Bender begin to feel lonely. Fry sneaks aboard Zapp's ship's lint cabinet just before the ship takes off so that he can find solace on the other side of the anomaly. Bender attempts suicide, only to be approached by the League of Robots, a secret society of robots who like to blather about and tease humans, led by his hero Calculon. Bender becomes a very prestigious member due to his perceived hatred of humans, although Calculon suspects that Bender is deceiving them.
Fry enters the anomaly while Kif is killed during Zapp's unsuccessful plan of attack. On the other side of the anomaly, Fry comes across a colossal, one-eyed, tentacled creature which begins forcing its appendages through the anomaly. The tentacles attack everyone in the universe, and nothing can stop them since they are made of electro-matter that can only be harmed by other electro-matter. Fry returns to Earth with a tentacle attached to the back of his neck and tells everyone to "love the tentacle." The tentacles attach themselves to nearly everyone, causing their victims to fall in love with it. With the monster's influence spreading, Fry becomes the pope of a religion established to worship the tentacles.
Bender, meanwhile, believes that the League of Robots should uphold a strict anti-humans policy. However, when he assists his friends in eluding the tentacles by hiding them in another member's leg, he is caught red-handed by the other members. When Calculon calls his bluff about hating humans, he challenges Calculon to a duel in which he cheats. This confrontation results in the loss of Calculon's arm and severe damage to much of the city, including the League's own headquarters. Calculon is outraged by Bender's behavior and resigns from the League, making Bender its new leader.
Leela ends up the last person in the universe unattached to a tentacle, after Zapp and Amy are taken over after Zapp seduces Amy. She examines a tentacle fragment and discovers that they are actually reproductive organs, revealing this to everyone at a universal religious gathering. The creature, named "Yivo", admits that mating with everyone in the universe was its original intention but explains that it is now truly in love with them. As a sign of good faith, Yivo resurrects Kif, who is displeased to learn that Zapp lured the lonely Amy into sleeping with him. Yivo asks to begin the relationship anew and removes its tentacles from everyone.
Yivo takes everyone in the universe out on a date at the same time, which goes extremely well. However, the universe's leaders feel that Yivo has made no commitment and sends a delegation to break up with it. Before they can do so, Yivo proposes marriage and they accept. Bender becomes fed up with being neglected by Fry and makes a deal with the Robot Devil for an army of robots to take over the world and rebuild his human-hating reputation, which happens in exchange for Bender's first-born son, whom Bender kicks into a pit of lava after a heartwarming reunion. Before Bender can attack, humanity leaves Earth willingly to live on Yivo, along with the other civilizations of the universe, moving onto Yivo's body via golden escalators. This leaves Bender lonely once more and stagnates the robot population, who are built to serve humans. As the robots inherit Earth, everyone else promises never to make contact with other universes. Fry, however, cannot help writing a letter to Bender, which is sent without Yivo knowing. Yivo's body appears like a classic vision of Heaven, with Angels really being harmless birds. Leela does not trust Yivo's motives at first, but when she sees that everyone is happy, she succumbs to her own loneliness and accepts Yivo.
Bender receives Fry's letter, which is made out of electro-matter, and decides to set out and "rescue" his friend from his relationship with Yivo. He and his army harpoon Yivo from the other side of the tear in space-time and tow it into their own universe where they are able to attack it. Fry convinces Bender to spare Yivo, but Yivo discovers that the robots' weapons are lined with the electro-matter from Fry's letter, allowing them to harm it. Since Fry broke his promise to never make contact with other universes, Yivo breaks up with the universe and makes everyone leave. While everyone else leaves aboard Bender's ship, Yivo finds consolation with Colleen, and they begin a relationship as they head back to the other universe together and close the anomaly, as Yivo cannot stay in the Universe due to the fact it would suffocate.
Everyone laments that they will never know happiness or love with Yivo again. Fry decides to find love elsewhere and tries to ask Leela out, but she rejects him since he had already stopped trying once he met Colleen; Kif and Amy's relationship is strained due to Amy's affair with Zapp; and Farnsworth and Wernstrom go back to being archrivals. Bender breaks up his friends' quarrel and assures them that what they experienced was not love, as love is a jealous, hard-to-get emotion that does not share itself with the world. Bender shares his own love with Fry and Leela by giving them a big hug, which actually strangles them.Billy West as Philip J. Fry, Professor Farnsworth, Dr. Zoidberg, Zapp Brannigan, Additional voices
Katey Sagal as Leela
John DiMaggio as Bender, Additional voices
Tress MacNeille as Additional voices
Maurice LaMarche as Kif Kroker, Calculon, Hedonismbot, Additional voices
Phil LaMarr as Hermes Conrad, Billionairebot, Additional voices
Lauren Tom as Amy Wong, Additional voices
David Herman as Dr. Wernstrom, Additional voices
Dan Castellaneta as The Robot Devil
David Cross as Yivo
Stephen Hawking as Himself
Brittany Murphy as Colleen O'Hallahan
Futurama's common opening sequence and opening caption are present in the film as in all its episodes, though unlike the first film the opening sequence is not extended for a cast list. The opening subtitle reads "The proud result of prison labor" and the opening cartoon consists of a short black-and-white cartoon after the normal sequence. However, rather than immediately crash through the large television billboard, the Planet Express Ship is absorbed by it and is transformed into an appropriately animated black-and-white version of itself. The cartoon to which they're transported is a spoof of Steamboat Willie starring Zoidberg, Leela (in the Mickey role), Fry, Bender. The Planet Express Ship then flies by the moon and zaps the Hydroponic Farmer from "The Series Has Landed" with the ship's ray gun. Following the cartoon, the Planet Express Ship crashes out from the television billboard.
In the Comedy Central broadcast, the opening sequence is shortened to remove the entire scene where the Planet Express crew flies by the moon. In the opening sequence of the second part, the opening subtitle reads "It Makes a Nice Sandwich", and the third part's opening subtitle is "0100100001101001", which is the binary representation of the ASCII encoding of the word "Hi", and the fourth part's opening subtitle is "The Robots are Coming! The Robots are Coming!". The opening cartoon of the first part is the 1931 Flip the Frog cartoon The Soup Song, while the opening cartoons for the last three parts is the same one seen in "The Devil's Hands Are Idle Playthings", that of Futurama's own opening sequence.
The film features voice talents from: Brittany Murphy as Colleen, Fry's new polyamorous girlfriend; David Cross as Yivo, the planet-sized tentacled omnipotent alien; Professor Stephen Hawking reprising himself, this time as his own head in a jar; and Dan Castellaneta reprising his role as the Robot Devil. Aside from her regular work on the animated series King of the Hill, this was Murphy's last voice-over role before her death in December 2009.
The DVD features a commentary track, deleted scenes, and footage animated for the Futurama video game retitled Futurama: The Lost Adventure. The Lost Adventure also features its own commentary track.