It has been 20 years since Lloyd Christmas and Harry Dunne embarked on their disastrous journey to Aspen. Now, life has taken unexpected turns for both of them, so when Lloyd finds out that he needs a kidney and that Harry has a daughter he never knew, the two friends decide to embark on a new and absurd adventure.
Lloyd, who had been in a mental institution for years pretending to be "a plant" due to a past emotional blow, reconnects with Harry at an impromptu meeting. Seeing a glimmer of friendship, they plan a trip to locate Harry's daughter, who turns out to be a rather unique young woman with her own issues. However, their plans quickly unravel as they face a series of ridiculous situations, including misunderstandings, silly jokes, and some pretty awkward moments.
The journey is filled with eccentric characters and moments that only those two can create, as they try to untangle a dark family secret that has been hidden for years. With each step they take, the antics become crazier and their friendship is put to the test. What starts as a trip to meet an unknown daughter turns into a race for redemption, with the hapless protagonists stumbling along the way, proving that, despite everything, friendship can still be the best medicine.