Eleven years after the events of the Clerks, Dante Hicks (Brian O'Halloran) opens the Quick Stop convenience store to find that it is on fire; Randal Graves (Jeff Anderson) had left the coffee pot on after closing the night before. As a result of the destruction of Quick Stop and the adjacent RST Video, Dante and Randal begin working at a Mooby the Golden Calf fast food restaurant along with Elias (Trevor Fehrman) and their manager List of View Askewniverse characters#Becky Scott (Rosario Dawson). A year later, Dante is planning to leave his minimum wage lifestyle in favor of a family life in Florida with his fiancée Emma Bunting (Jennifer Schwalbach Smith), whose father will provide them with a home and a business to run. This leaves Randal, who fears that with Dante moving to Florida would leave him without his best friend, bitterly disappointed. Jay and Silent Bob (Jason Mewes and Kevin Smith) have since followed Dante and Randal, and now loiter outside of Mooby's. Jay and Silent Bob no longer do drugs after they were arrested for possession and were sent to Drug rehabilitation, and become devout Christians following their release. However, the duo continue selling drugs.

As a cowardly farmer begins to fall for the mysterious new woman in town, he must put his newly found courage to the test when her husband, a notorious gun-slinger, announces his arrival.

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.

Scott has been a case of arrested development since his firefighter dad died. He spends his days smoking weed and dreaming of being a tattoo artist until events force him to grapple with his grief and take his first steps forward in life.

Agent J travels in time to M.I.B.'s early days in 1969 to stop an alien from assassinating his friend Agent K and changing history.

A group of intergalactic criminals must pull together to stop a fanatical warrior with plans to purge the universe.