Two years after The Hangover Part II, Leslie Chow escapes from a maximum security prison, using a riot as cover. Meanwhile, in the United States, Alan Garner causes a multi-car freeway pileup after he purchases a giraffe and accidentally decapitates it on a low overpass. Alan's father Sid, angry with Alan for his immature antics and never owning up to his mistakes, dies of a heart attack in the middle of a lecture. After the funeral, Alan's brother-in-law Doug Billings informs friends Phil Wenneck and Stu Price that Alan has been off his Attention deficit hyperactivity disorder medication and is out of control. The group attends an intervention in which Alan agrees to visit a rehabilitation facility in Arizona where he can seek treatment, as long as "the Wolfpack" takes him there. On the way to Arizona, Phil's minivan is rammed off the road by a rental truck and the group is taken hostage. They are later confronted by mob boss Marshall and "Black Doug", his head enforcer.

Adam Jones is a chef who destroyed his career with drugs and diva behavior. He cleans up and returns to London, determined to redeem himself by spearheading a top restaurant that can gain three Michelin stars.

Having both coincidentally cheated death on the same day, estranged twins reunite with the possibility of mending their relationship.