Carl Fredricksen (Jeremy Leary) is a shy and quiet boy who has long idolized renowned explorer Charles F. Muntz (Christopher Plummer). He learns, however, that Muntz was accused of fabricating a giant bird skeleton he had discovered in Paradise Falls, South America, forcing him to return there to capture one alive. One day, Carl befriends an energetic tomboy named Ellie (Elizabeth Docter), who is also a Muntz fan. Detailing her ambitions in her personal scrapbook, she tells Carl of her desire to move her clubhouse to a majestic waterfall cliff in Paradise Falls. She makes him promise to help her, which he does.

Carl and Ellie eventually get married and grow old together in the old house where they first met, working as a toy balloon vendor and a zookeeper, respectively. Unable to have children, they repeatedly try to save up for the trip to Paradise Falls, but other financial obligations arise. Just as they're finally about to make the voyage, Ellie becomes ill and dies, leaving Carl a lonely and bitter widower.

As the years pass, the city grows around the now elderly Carl's (Edward Asner) house. Refusing to move, he soon ends up in a tussle with a construction worker over his broken mailbox, resulting in a court order to move him into a retirement home. However, he comes up with a scheme to keep his promise to Ellie: he turns his house into a makeshift airship, using tens of thousands of helium balloons to lift it off its foundations. A young Wilderness Explorer, Russell (Jordan Nagai), is accidentally caught on Carl's porch, after trying to earn his final Merit Badge for "assisting the elderly".

After getting caught in a thunderstorm, they find themselves landing near a large ravine facing Paradise Falls. With their body weight keeping it from floating away, Carl and Russell harness themselves to the house and begin to walk around the ravine, hoping to reach the falls before the balloons deflate. They later encounter a tall and colorful flightless bird, who is trying to return to her chicks. Russell names the bird Kevin and makes Carl promise to help return her safely to her brood.

The group then meets a dog named Dug (Bob Peterson), who wears a special collar that allows him to speak. Carl and Russell learn that his owner is an elderly Charles Muntz. Muntz has been at Paradise Falls all these years trying to capture the giant bird, who happens to be Kevin. Muntz invites Carl and Russell onto his dirigible, and, although Carl is initially thrilled to meet his childhood hero, Russell innocently reveals his friendship with Kevin. Carl, Russell, Dug and Kevin escape from Muntz and his army of vicious dogs, but Kevin is injured during the escape. The group agrees to assist Kevin, which allows Muntz and his dogs to catch up with them. Muntz then starts a fire beneath Carl's house, making Carl choose between saving his house or saving Kevin. He chooses to save his house, allowing Muntz to capture the bird and take him away. Carl eventually reaches the falls, but Russell has become angry with Carl over him deserting Kevin.

Finally settled into his home, Carl is sadly pondering over Ellie's childhood scrapbook when, to his surprise, he discovers photos of their married life added in the formerly blank pages, and a final note from Ellie encouraging him to go on a new adventure. Invigorated, he goes to find Russell, only to see him flying away, with the aid of a leaf blower and some balloons, to save Kevin. Carl lightens the weight of his house by dumping his old furniture and other sentimental possessions, allowing him to give chase.

Russell ends up being captured, but Carl arrives just in time to save him and free Kevin. Muntz then pursues them around the airship. He manages to corner Dug, Kevin and Russell, with a hunting rifle, inside the house, while Carl is outside trying to anchor it down. Carl then lures Kevin through a window with a chocolate bar, as Dug and Russell hang onto her back. Muntz leaps out after them, only to snag his foot on some balloon lines, and fall to his death. Snapped from its tether, the house descends below the clouds and out of sight.

Carl takes Muntz's dirigible, returning Kevin to her chicks, then flying back to the city. When Russell's father misses his son's Senior Explorer ceremony, Carl fulfills that role himself, to proudly present Russell with his final badge: the grape soda cap badge that Ellie gave to Carl when they first met. Russell adopts Carl as his father figure, while Dug takes to him as his new master. As the three set out on many new adventures, the house is shown to have landed perfectly on the cliff over Paradise Falls.

Marlin, an Ocellaris clownfish, takes extra care of his only child, Nemo, after his wife Coral and the rest of their eggs were eaten by a barracuda. Due to a crack in Nemo's egg, he has grown up with one small, weak fin, but which Marlin assures him is his "lucky fin". On the first day of school, the other kids tease Nemo about his overprotective widower father. Nemo decides to swim into the open waters to prove that he is capable but is quickly captured by a scuba diver, who climbs aboard a boat and drives off. Marlin is unable to keep up after a frantic chase but meets Dory, a regal tang with short-term memory loss. Together they discover a diver's mask on the ocean floor dropped from the boat, and Dory is able to read the address on it as being Sydney, Australia. The two set off; Marlin's story of determination quickly spreads about the oceans, and various sea creatures quickly give aid to his search.

Meanwhile, the diver, a dentist, returns to his office and places Nemo in a fish tank. Nemo meets the other fish, led by the Moorish idol Gill. When they realize that the dentist plans to give Nemo to his niece Darla, who has had a fateful history of dealing with pets before, they devise a plan to help free Nemo by forcing the tank to become dirty, requiring the dentist to remove the fish and allowing for their escape. The plan requires Nemo, the smallest of them, to swim up the water filter and disable it; the first attempt is nearly fateful for Nemo, but is able to succeed on a second attempt when he hears from Nigel, a Brown Pelican, that Marlin is coming for him. However, the plan backfires, as the dentist installs an automatic tank cleaner the next day, and Nemo becomes dejected. After several adventures, Marlin and Dory arrive in Sydney and are met by Nigel, who takes them to the dentist's office, but find the dentist is already getting ready to give Nemo to Darla. Nemo acts dead as to force him to be flushed down the drain and eventually into the sea, but this also causes Marlin to believe him to be dead. After Nigel's presence in the office causes a small pandemonium, Gill helps Nemo to escape down a drain.

Despite the fact that Dory claims to have better memory when around him, Marlin tells Dory to leave him alone once they are back in the sea. Dory swims off but encounters Nemo; though temporarily confused due to her memories, she eventually remembers Marlin's goal, and helps Nemo back to his father. The two, along with Dory, happily celebrate, but their joy is quickly cut short when Dory is caught, along with a school of grouper, in a fishing net. Despite Marlin's worries, Nemo swims to help the fish, including Dory, escape using a trick taught to him by Gill and the other aquarium fish. The three return back home, with Marlin less protective of Nemo now aware of his son's abilities; Nemo's stories of his adventures impress the other children, while Marlin is seen as an outstanding father by the other fish. Meanwhile, Gill and the other fish from the dentist's office have managed to make their escape via their original plan, ending up safely in the ocean but still in plastic bags.

Remy is a rat who lives in the attic of a French country home with his brother Emile and a pack led by his father Django. Gifted with a keen sense of smell and taste, Remy aspires to be a gourmet chef, inspired by France's recently deceased top chef, Auguste Gusteau, but instead his talent is put to work in sniffing for rat poison. When the pack is discovered by the home's occupant, they flee into the sewers; Remy becomes separated from the others and ends up marooned underneath Gusteau's restaurant in Paris, conversing with a hallucination of the famous chef.

Urged on by Gusteau, Remy makes his way up to the restaurant's kitchen skylight to watch the staff in action. There, he observes Alfredo Linguini being hired as an escuelerie by Skinner, the restaurant's current owner and Gusteau's former sous-chef. When Linguini spills some of the soup and attempts to recreate it using random ingredients, Remy is horrified, and falls into the kitchen; there, instead of escaping, he fixes the soup. Remy is caught by Linguini just as Linguini is caught by Skinner, but before anyone can stop the serving staff, the soup is served and found to be a success. Colette, the staff's only female chef, convinces Skinner to retain Linguini, believing him to be the success behind the soup. Linguini takes Remy home instead of killing him, as Remy was the "little chef" who made the soup.
Remy discovers that he can control Linguini's movements by pulling on his hair.

Remy and Linguini find a means to overcome their language barrier, with Remy pulling Linguini's hair under his toque blanche to control his limbs like a marionette. The pair successfully meet the challenges devised by Skinner. Skinner, suspicious of Linguini's talents, discovers that Linguini is actually Gusteau's son and by Gusteau's will, is the rightful owner of the restaurant; this revelation would ruin Skinner's plans to use Gusteau's name to market a line of microwaveable meals. Remy discovers the documents and takes them to Linguini, who subsequently fires Skinner and takes control of the restaurant. Linguini and Colette even begin to develop a romantic bond, leaving Remy feeling left out and taken for granted. Remy finds Emile in the restaurant's trash, and Remy is reunited with the pack. Django warns Remy that humans and rats will never get along, but Remy does not believe him. Meanwhile, Remy begrudgingly feeds Emile and his friends by stealing from the kitchen's pantry as the nights pass.

Anton Ego, a food critic whose past review cost Gusteau's one of its star ratings, announces he will review the restaurant again the next day based on its rising success. Linguini, under pressure of Ego's pending arrival, has a falling out with Remy, causing Remy to retaliate by leading a raid on the kitchen's foodstocks that night. Linguini catches the rats in the act and chases them all out, including Remy, telling the rat he never wants to see him again. Remy, dejected, is captured by Skinner. In his cage, Remy has one final conversation with his phantom Gusteau, who tells him that the rat never needed his guidance and at that moment, he is freed by Django and Emile. Remy returns to the kitchen, where a frantic Linguini apologizes and asks Remy back to help. Linguini then reveals the truth about Remy to the staff, resulting in a mass walk-out by the heartbroken disbelievers; Colette later returns after recalling Gusteau's motto: "Anyone can cook."

Impressed by his son's determination, Django organizes the rest of the pack to help out in the kitchen. They throw Skinner and a health inspector, bound and gagged, into the freezer when they try to interfere. Linguini uses roller skates to wait on all the tables by himself, while Remy and Colette work together to prepare a variation on ratatouille for Ego. Ego is amazed by the dish, which evokes childhood memories of his mother's cooking, and asks to see the chef. Linguini and Colette wait until all the other customers leave to introduce Remy to Ego. Ego writes a glowing review of the meal the next day, declaring Remy to be "nothing less than the finest chef in France."

In the dénouement, Gusteau's is closed down by the health inspector, and Ego loses his job and his credibility as a food critic for praising a restaurant filled with rats. However, he eagerly funds a new restaurant run by Linguini and Colette, featuring dining areas for both humans and rats and a kitchen designed for Remy to continue cooking. The film ends showing a long queue outside and a sign displaying a rat wearing a toque and holding a spoon, above it the name "La Ratatouille."

The extended lace curtain Irish-American McCallister family prepares to spend Christmas with Peter and Frank's brother in Paris, France, gathering at Peter and Kate's home in Chicago the night before their flight. Eight year old Kevin, Peter and Kate's youngest son and the protagonist of the film, finds himself the subject of ridicule from the other children. After getting into an argument with his older brother Buzz because he ate Kevin's cheese pizza on purpose, he is sent to the third floor of the house, wishing his family shall disappear. The family accidentally leaves Kevin asleep in bed, as a power outage resets the time and causes them to wake up four hours late and a neighbor boy named Mitch Murphy who also leaves for vacation to Missouri is mistaken for Kevin in a headcount, and they hastily depart to the Chicago O'Hare International Airport, for a flight to Paris-Orly Airport onboard a McDonnel Douglas DC-10. During the flight, Kate realizes that they have left Kevin behind, and once everyone is in Paris, she immediately tries to book a return flight back to Chicago. Kate manages to fly into Dallas and Scranton, Pennsylvania, but the flight to Chicago was out of order. However, she does manage to hitch a ride with a man named Gus Polinski and his polka band, the Kenosha Kickers, who are driving to Milwaukee after their flight was canceled in a blizzard.

Meanwhile, Kevin wakes up to find the house empty and is overjoyed to find that his wish came true. He gets away with taking Buzz's life savings, shooting Buzz's gun, jumping on the bed, watching a gangster film, and eating a large amount of junk food. However, Kevin finds himself scared by the appearance of the Chicago Police Department (called by his parents to check on Kevin via payphone from Paris-Orly), his next door neighbor "Old Man" Marley, who was rumored to have murdered his family many years earlier, and the appearance of The Wet Bandits, Harry Lyme and Marv Merchants, who are breaking into other vacant houses along the block. The Wet Bandits are aware of which houses are vacant, as Harry impersonated a police officer doing wellness checks on families before the holidays. On Christmas Eve, Kevin manages to overhear Harry and Marv discuss plans for breaking into his house that night. After conversing with a Santa Claus impersonator and watching a local choir perform in a church in hopes to have his family return, Kevin runs into Marley and comes to realize that he is a nice man and that none of the rumors about him are true. Kevin finds out that Marley is estranged from his son and suggests that he reunite with him for Christmas.

His own spirits lifted by encouraging Marley, Kevin returns home to prepare a series of booby traps about the house. Harry and Marv, who were initially fooled by Kevin's illusions that the house is occupied but now realize that he is home alone and attempt to break in, running into the various traps. After the two spring almost every trap in the house, Kevin flees to the third floor of the house, and dials 9-1-1 from a landline. Harry and Marv manage to chase Kevin out of the house; he then flees to the vacant neighboring home, which was unlocked and unoccupied. The Wet Bandits trap Kevin when he runs to the top of the stairs connecting the basement and the first floor. They decide to do the same things that Kevin did to them and Harry decides to bite Kevin's fingers one at a time first, but Marley knocks them out with his snow shovel and takes Kevin home. Shortly after Kevin is safely returned home, Harry and Marv are arrested. Additionally, the police were aware of every house The Wet Bandits have hit due to their habits of leaving the household's water running to leave their mark.

Kevin wakes up the next morning to find that his mother has returned. Shortly afterward, the rest of the McCallisters, having traveled directly to Chicago from Paris, arrive. Kevin keeps silent about his encounter with Harry and Marv, but Peter finds Harry's missing gold tooth and wonders what it is. Kevin and Buzz have a moment and it looks like they will finally start to get along. Kevin discovers that Marley took his advice and watches from the window as he and his son reunite, smiling. However, Buzz interrupts Kevin's musings by yelling the line, "Kevin! What did you do to my room?!". Immediately following it, the film ends.