Young Carl Fredricksen idolizes famous explorer Charles F. Muntz, who when accused of fabricating the skeleton of a creature he brought back from Paradise Falls in South America, leaves and vows not to return until he has captured one alive. Carl meets a girl named Ellie, also a Muntz fan, who confides her desire to move her "clubhouse"—an abandoned house in the neighborhood—to a cliff overlooking Paradise Falls. The two later marry and live in the restored house, and Carl works as a balloon salesman. Suffering a miscarriage and unable to have children, they decide to save up to go to Paradise Falls, but are constantly forced to spend their savings on more urgent needs. Now an elderly couple, Carl finally arranges for the trip, but Ellie falls ill and dies.
Years later, Carl, now retired, stubbornly holds out in the house while the neighborhood around him is replaced by skyscrapers. When he accidentally injures a construction worker, the court deems him a public menace and orders him to move to a retirement home. However, Carl resolves to keep his promise to Ellie to go to Paradise Falls, turning his house into a makeshift airship using thousands of helium balloons and flying away. Russell, a young "Wilderness Explorer" who visits Carl in an effort to earn his final merit badge for assisting the elderly, becomes an accidental stowaway. Before Carl can land and return Russell, they encounter a storm which drives them all the way to South America.
The house lands on a tepui opposite Paradise Falls. Carl and Russell harness themselves to the still-buoyant house and begin to walk it across the mesa, hoping to reach the falls before the balloons deflate. Russell encounters a tall, colorful flightless bird whom he names "Kevin". They then meet a Golden Retriever named Dug, who wears a special collar that allows him to speak and who vows to take the bird to his master. The next day, they encounter a pack of aggressive dogs led by Alpha, a Doberman Pinscher, and are taken to their master, who turns out to be the elderly Charles Muntz. Muntz invites Carl and Russell aboard his dirigible, where he explains to them that he is searching for a giant bird. When Russell notes the bird's similarity to Kevin, Muntz becomes hostile, believing they are attempting to capture the bird themselves.