Two years after the events in the previous film, the Baker family begins to undergo many changes, beginning with Lorraine (Hilary Duff) and her desire to study in New York. Their oldest daughter Nora (Piper Perabo) is now married to Bud McNulty (Jonathan Bennett) and heavily pregnant. They intend to move to Houston because of Bud's new job promotion.
Teenage friends Will McKenzie, Simon Cooper, Jay Cartwright, and Neil Sutherland have finished their A-levels and are about to leave Rudge Park Comprehensive, much to the relief of Mr. Gilbert, their sardonic sixth form tutor. Within their final week of school, Jay's grandfather dies, Simon is dumped by his girlfriend Carli D'Amato, and Will's divorced father tells him he has married his much younger mistress. The boys decide to go on holiday together and Neil books them a trip to Malia, Crete.
Bob Munro (Robin Williams), a successful California beverage company executive, is struggling with a dysfunctional family, with his materialistic wife Jamie (Cheryl Hines), his sharp-tongued teenage daughter Cassie (JoJo), and his son Carl (Josh Hutcherson), who is an adolescent weightlifter and likes Hip hop. At a company picnic, Bob is embarrassed in front of his self-absorbed boss Todd (Will Arnett) by Cassie's militant friend Gretchen, who hurls a tub of disgusting slime over Todd. Looking forward to a big family vacation in Hawaii, their trip is cancelled when Todd, out of spite, tells Bob that he has to attend a meeting with the Alpine Soda company in Boulder, Colorado instead, or else he will be fired. Concealing the real reason for going there, he rents a garish RV from the dodgy dealer Irv (Barry Sonnenfeld) and tells his family they are traveling to the Rockies.
The characters from the first two films get together again, 27 years on, in Sardinia. The obsession with sex has not disappeared but has taken a backwards step in the face of financial preoccupations. Bernard and Nathalie Morin (Gérard Jugnot, Josiane Balasko), are the parents of a son who reveals a homosexual liaison; J.C. (Michel Blanc) and Gigi (Marie-Anne Chazel), are living together; Jérome Tarayre (Christian Clavier), is divorced and seems unhappy in his new life; Christiane Weissmuller (Dominique Lavanant), has joined an esoteric sect and wants revenge on Jérome who messed up an operation he performed on her; Popeye (Thierry Lhermitte), has become the proprietor of the hotel where the group has re-assembled, and is as unfaithful as ever.
The Heffley family attends a pool party at the local pool, where the family meets a former trouble-making friend of Rodrick (Devon Bostick) who is now a model student after attending a military school known as Spag Union, into which Greg's dad Frank (Steve Zahn) thinks about joining Greg.
In the Victorian period, two young cousins, Richard and Emmeline Lestrange, and a galley cook, Paddy Button (Leo McKern), survive a shipwreck in the South Pacific and reach a lush tropical island. Paddy cares for the small children and forbids them by "law" from going to the other side of the island, as he found evidence of remains of bloody human sacrifices. He also warns them against eating a scarlet berry which is apparently deadly.
In the summer following their first year of college, we revisit four friends who have been apart all year and plan to spend their summer apart until a magical old pair of pants reunites them. Bridget (Blake Lively) visits her grandmother Greta (Blythe Danner) in Alabama to ask about her mother's suicidal depression. Lena (Alexis Bledel) finds her former flame Kostas (Michael Rady) married in Greece. Tibby (Amber Tamblyn) goes through a pregnancy scare and alienates Carmen. Carmen (America Ferrara) auditions for Perdita in a Vermont acting workshop. When Lena's sister Effie (Lucy Hale) steals and loses the Pants in Greece, the Sisterhood follows.
Tripper Harrison (Murray) is the head counselor of a group of new counselors-in-training (CITs) at Camp North Star, a cut-rate summer camp. Camp director Morty Melnick (Atkin) falls victim to Tripper's practical jokes mainly by being taken from his cabin in the middle of the night and being relocated to an unusual place such as in a hammock above the trees or along the roadside outside of camp.
Four teenage girls — Carmen, Tibby, Bridget, and Lena — are best friends from Bethesda, Maryland, who are about to separate for the summer for the first time in their lives. Lena is spending the summer in Greece with her grandparents; Tibby is staying at home; Bridget is going to soccer camp in Mexico; and Carmen is visiting her father in South Carolina. On one of their final days they went shopping together, the girls find a seemingly ordinary pair of jeans that fit them all perfectly and flatter their figures, despite their very different measurements. The girls dub them the Traveling Pants and decide to share them equally over the course of the summer. They part the next day, and the film focuses on each girl's journey separately.
Overworked air traffic controller Jack Chester (Candy) is given four paid weeks off as an alternative to being fired after nearly causing a mid-air collision on the job. He uses this time off to take his wife Sandy and children Jennifer, Bobby, and Laurie on a summer vacation from the Atlanta area to the Gulf Coast resort town of Citrus Cove, Florida, where they are constantly beset by a never-ending barrage of problems. First they are bumped out of the front of the line of an upscale seafood restaurant in favor of arrogant local sailing champion Al Pellet; who, because of this incident, becomes Jack's main nemesis throughout the film. Shortly after, by a misreading of the address; the family discovers that they have moved into the wrong house and are forced to move out in the middle of the night, ending up in a decrepit shack on a public beach with a constant stream of beach-goers tromping through. Jack then receives a leg injury that prevents him from spending time with his family.
Nicholas spends his summer holidays with his is parents and Grandma at the seaside. He quickly makes new friends, including the girl Isabelle who lives in the area, the English pupil Djodjo, the gourmand Fructueux, the righteous Côme and the crybaby Crépin. But just when Nicholas believes he's got everything under control, Isabelle appears. He doesn't understand why she cares so much about him until he becomes suspicious that his parents are trying to set her up as his wife-to-be.
Georgia (Nia Vardalos) is a Greek American tour guide who is leading a tour around Greece with an assorted group of misfit tourists who would rather buy a T-shirt than learn about history and culture. In a clash of personalities and cultures, everything seems to go wrong, until one day when an older traveller named Irv Gideon (Richard Dreyfuss), shows her how to have fun, and to take a good look at the last person she would ever expect to find love with, her Greek bus driver (Alexis Georgoulis).
Gigi, Jerome, Christiane, Jean-Claude, and Bernard visit a resort in the Ivory Coast, the Club Med village of Assinie. Bernard subsequently meets up with his wife, Nathalie, who has already spent a week there, and they are all welcomed by Popeye and the eccentric emcees, Bobo and Bourseault.