Gaylord "Greg" Focker (Ben Stiller) is a nurse living in Chicago. He intends to propose to his girlfriend Pam Byrnes (Teri Polo), but his plan is disrupted when he learns that Pam's sister's fiance had asked Pam's father for permission before proposing. Greg and Pam travel to Pam's parents' house to attend Pam's sister's wedding. Greg hopes to propose to Pam in front of her family after receiving her father's permission. But this plan is put on hold when the airline loses his luggage, including the engagement ring.
At the Byrnes' home on Long Island, Greg meets Pam's father Jack (Robert De Niro), mother Dina (Blythe Danner) and their beloved cat Mr. Jinx. Jack takes an instant dislike to Greg and openly criticizes him for his choice of career as a male nurse and whatever else he sees as a difference between Greg and the Byrnes family. Greg tries to impress Jack, but his efforts fail completely. Greg becomes even more uncomfortable after he receives an impromptu lie detector test from Jack and later learns from Pam that her father is a retired CIA counterintelligence officer.
Meeting the rest of Pam's family and friends, Greg still feels like an outsider. Despite efforts to impress the family, Greg's inadvertent actions make him an easy target for ridicule and anger: He accidentally breaks Pam's sister's nose during a water volleyball mishap; uses a malfunctioning toilet that floods the Byrnes' back yard with sewage; sets the wedding altar on fire and inadvertently leads Jack to think he is a marijuana user. Later, Greg loses Jinx and replaces him with a stray whose tail he spray paints to make him look like Mr. Jinx. The stray cat trashes the house, and the Byrnes' arrive at the scene.
By now, the entire Byrnes family, including Pam, agrees that it is best for Greg to leave. Unwillingly, Greg goes to the airport where he is detained by airport security. Back at the Byrnes household, Jack tries to convince his wife and Pam that Greg would be an unsuitable husband. Upon receiving retribution from both his wife and Pam, Jack realizes that Pam truly loves Greg. Jack rushes to the airport, convinces airport security to release Greg and brings him back to the Byrnes household.
Greg proposes to Pam. She accepts, and her parents agree that they should now meet Greg's parents. After Debbie's wedding, Jack views footage of Greg recorded by hidden cameras that he had placed strategically around their house.