Greg Focker is now a parent of two kids and tries to balance his career as a male nurse with his responsibilities at home. His father-in-law, Jack Byrnes, still has doubts about Greg's capabilities and suitability as the head of the family. Jack's skepticism intensifies when he goes through a minor health scare and looks for someone to take over as the family's patriarch, a role he dubs "The Godfocker." Determined to prove himself, Greg takes on additional work with a pharmaceutical company, introducing him to Andi Garcia, a beautiful drug representative, which only fuels Jack's suspicions about Greg's fidelity and professionalism.

Tensions rise as Greg's attempts to impress Jack continue to go awry, leading to a series of comedic misunderstandings and mishaps. The situation escalates with the arrival of Kevin, Pam's ex-fiance, who continuously impresses Jack and Pam's family. Through a series of humorous yet heartfelt events, Greg strives to win Jack’s approval and solidify his place within the family. As he navigates the chaotic landscape of parenting, professional hurdles, and familial expectations, Greg must prove that he is deserving of Jack's trust and ultimately show that his family comes first.