Five years after the prior film's events, Greg Focker and his wife Pam prepare to celebrate their twins Samantha and Henry turning five. However, trouble brews when Pam's parents, Jack and Dina Byrnes, come to visit. Jack reveals he is on the lookout for a successor to take over the Byrnes family legacy.
Recently diagnosed with a heart condition, Jack has been feeling disillusioned, particularly after his daughter Debbie divorced her husband Bob—whom Greg met when he first married Pam—due to his infidelity with a nurse. Initially considering Bob for the role, Jack unexpectedly selects Greg, dubbing him "The Godfocker."
Though Greg accepts this new title with reluctance, Jack remains skeptical of his abilities. He grows increasingly suspicious of Greg, mistakenly interpreting a flirtation with the drug representative Andi Garcia as infidelity. Compounding the issue is Greg’s association with Sustengo, an erectile dysfunction drug he promotes on the side, which leads Jack to question his sexual attraction to Pam. Jack's doubts extend further when he expresses hesitation about sending the twins to a private school, thereby questioning his financial capabilities.
While promoting Sustengo at a medical conference, Greg encounters Bob at a bar, where he learns of Jack’s initial plan to name Bob “The Bobfather” as his successor. Although Greg feels a sense of relief at the thought of escaping the Byrnes legacy, it also leaves him unsettled. Meanwhile, Jack seeks to persuade Pam to leave Greg and rekindle her relationship with her ex-fiancé Kevin Rawley, whom he believes to be a better match for her.
After a heated confrontation with Jack at a clinic, Greg retreats to their new, unfinished home, where Andi unexpectedly arrives. She attempts to lift his spirits with Chinese food and wine but eventually makes an overzealous pass at him after consuming too much and taking Sustengo.
Just as Greg tries to refuse Andi's advances, Jack arrives at the house looking to apologize. Peering through the window, he misinterprets the situation as Greg and Andi engaged in a sexual encounter, prompting him to leave, outraged.
The next day, Greg's parents, Bernie and Roz, join the family for the twins' birthday. Enraged by what he believes to be Greg’s infidelity, Jack confronts him, leading to a physical altercation, which culminates in Jack suffering a heart attack. In the crisis that follows, Greg takes charge, demonstrating his quick thinking as he assists Jack.
As Jack is whisked away by paramedics, he quietly acknowledges his belief in Greg after seeing his stable carotid artery, leading him to approve of Greg as "The Gregfocker."
Fast forward four months to Christmas Day, where Greg and Pam’s parents merge to celebrate the holidays in their new home. In a surprising twist, Greg's parents present Jack with a kippah, claiming to have traced Jack's family history, revealing his Jewish roots. Additionally, Bernie and Roz share their plans to move closer to Greg and Pam, as do Jack and Dina, who wish to be near their grandchildren.
In a humorous closing scene, Jack is seen watching YouTube videos where Greg humorously ridicules him during a Sustengo promotional speech.
