Greg Focker, portrayed by Ben Stiller, and his wife Pam, played by Teri Polo, are caught in the hustle and bustle of a typical morning as they prepare their two children for school. While at work, Greg receives an unexpected visit from Andi Garcia, a former nurse now representing a male enhancement drug named Sustengo. Andi, impressively portrayed by Jessica Alba, tries to persuade Greg to become the spokesperson for Sustengo, enticing him with the promise of a higher salary. Intrigued, Greg takes Andi's card, leaving the door open for consideration.
In another part of town, Jack Byrnes, played by Robert De Niro, and his wife Dina, depicted by Blythe Danner, are discussing the fallout from their daughter’s marriage to Dr. Bob, who cheated on her. As Dina plans to visit their daughter, Jack faces a health scare that culminates in a minor heart attack. He manages to contact emergency services and surprisingly pulls through.
Later that evening, during dinner at the Focker household, Greg receives a distressing call from Jack. Jack reveals his heart attack and unexpectedly appoints Greg as the new head of the family, humorously dubbing him the "Godfocker." He cautions Greg to keep this news a secret from Dina and the kids. Filled with a newfound sense of power, Greg convinces Pam to schedule a tour for The Early Human School, a prestigious private institution they are considering for their children.
Fast forward two weeks, Jack and Dina pay a visit to the Fockers. During a chaotic dinner, Greg’s son’s pet lizard startles him as he carves a turkey, leading to an unfortunate mishap that leaves blood splattered on the guests. Soon after, Kevin, portrayed by Owen Wilson, arrives, heartbroken after a breakup, and while Pam offers him a place to stay, he insists he’ll be fine.
The next day, as Pam falls ill, Jack accompanies Greg to the school tour. Their presence is hilariously misinterpreted, with people assuming they are a homosexual couple. Ultimately, Greg decides to accept Andi's offer to be the spokesperson for Sustengo and plans to deliver a speech at a hotel. He cautiously informs Pam but asks her not to mention it to her dad. Unfortunately, their daughter overhears this and innocently tells Jack that Daddy will be meeting a woman who helps him with "boners," causing Jack to suspect infidelity.
That evening, Jack discretely follows Greg, leading to a humorous confrontation at the metro station. Meanwhile, Greg’s presentation at the hotel goes splendidly, resulting in numerous congratulations and photos with Andi. However, when Jack returns home and finds samples of Sustengo, he becomes convinced of a scandalous affair.
Amidst the chaos, Greg plans a birthday party for the twins at his new house, but a construction mishap derails those plans. Instead, Kevin offers his larger home for the celebration. The family visits the Early Human School for evaluations. While the girl performs admirably, the boy struggles, leading Jack to casually remark that she takes after Pam while the boy mirrors Greg.
When an accident sends their son to the hospital with a broken arm, Jack uses this moment to suggest Pam should leave Greg for Kevin, intensifying the tensions. Following a heated argument with Jack, Greg takes refuge at his new house, where Andi unexpectedly appears with Chinese food. A drunken encounter ensues, leading to a kiss from Andi that Greg rebuffs. Misunderstandings deepen when Jack arrives to apologize, but seeing them together again, he leaves, now convinced of the affair.
As the twins' birthday party unfolds at Kevin's place, tensions mount. An altercation breaks out when Greg attempts to mend fences with Jack, resulting in a physical fight. Their brawl is interrupted when Mr. Jinx, Jack’s cat, tries to eat their son's pet, further escalating Jack’s health issues. Ultimately, Greg rushes to support Jack during a heart attack episode, and upon being whisked away in an ambulance, Jack finally accepts Greg’s innocence, humorously promoting him to "Gregfocker."
The film concludes with a light-hearted gathering where Greg, Pam, and their families enjoy each other's company. However, the peace is quickly disrupted when Greg's parents announce their decision to move nearby, prompting Pam's parents to make a similar declaration, leading to comedic chaos as Greg and Pam panic over their family's seemingly never-ending entanglements.
