Ten years have passed, and Sidney Prescott, who has put herself back together thanks in part to her writing, is visited by the Ghostface Killer.

A night debauchery in Las Vegas goes massively awry when three groomsmen lose their best friend during his bachelor party, just days before his impending wedding.

The first scene shows Agent Sam Stanley and Agent Chet Desmond late at night after performing the autopsy on the body of List of Twin Peaks characters#Teresa Banks as they discuss how much time had passed since they entered the morgue. Later, they arrive at Hap’s Diner, where Teresa once worked the night shift as a waitress, and question the owner of Hap’s about Teresa. Sheriff Cable of Deer Meadow goes outside with Desmond, and fights him over taking the body of Teresa with him back to Portland, which took the murder investigation out of the hands of the local and corrupt Police Department. Later, Special Agent Dale Cooper is shown in a doorway in the Philadelphia headquarters of the FBI talking to his secretary Diane. Next, Cooper meets Sam Stanley after Desmond went missing.

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.