Set some time after the events of the first film, Murphy John Durfy, Jr. has died, and Josh Duhamel as Bobfather, Nick Swardson as Bender, and Kevin Dillon as Doc, along with their friend Zane, attend the funeral. Durfy's brother, Jack, prepares to take Durfy's ashes to the family business, where he intends to scatter them. However, Bobfather, wanting to scatter the ashes in a place that is more sentimental to their friendship, steals the urn and plays a game of keep away with it. They flee the church with the urn and escape in a helicopter with their friend Dan Bakkedahl as Shelly, but Jack and his uncle Tommy pursue and attack Zane on foot. The guys resolve to scatter the ashes at the lake where they first invented the Buddy Games.
The guys arrive at Party Marty’s, the bar they invented the games at and are banned from for life. The guys are shocked to see that the owner, Marty, has stolen their idea and has been doing it ever since. The guys participate in the Buddy Games to regain their crown, only to be beaten by some underhanded tactics by an opposing team. Although they lose the games, they earn the respect of Marty, who buries the hatchet with the guys. Marty informs the guys that Celia, Durfy's love, is played by Ginnifer Goodwin and lives in Backwater, a nearby town. The guys decide to scatter the ashes with her the next day. Marty informs the guys that there are no vacancies in the area because of spring break.
However, they are approached by Phoenix, a mysterious new-age woman, Carmel Amit who invites them to her rave and offers to make sure they have a place to sleep. With no other options, the guys go to Phoenix's rave where they are given a warm welcome, but their old-fashioned ways clash with the new, "woke" attitudes of the younger party attendees. Thinking they are Shiitakes, Doc eats ten Psilocybin mushrooms by mistake. Not wanting their friend to have a trip alone, all of the guys take various recreational drugs and become extremely high. After a night of hardcore partying, the guys become separated and pass out.
The next morning, the guys realize that their group has split into two. Bobfather and Bender wake up in a spare room in Phoenix's house and realize that she runs a cult and intends to indoctrinate them into her philosophy. Doc and Shelly wake up in a brothel and Doc realizes that he had sex with a prostitute the previous night. Doc and Shelly are unable to get ahold of the other two, so they decide to start walking towards Backwater, followed by a chicken Doc names "Henrietta". Back at the cult, Phoenix tells Bobfather and Bender that the purpose of her cult is to take the rejects of society and re-educate them. She specifically targets "alpha males" in hopes of giving them an awareness of social inequalities. Phoenix puts the two into her own version of the Buddy Games, a series of escape rooms that educate the participants on leftist social ideology. The guys reluctantly pass all the tests, only for Phoenix to force Bobfather to play an "adult game", Russian Roulette with a loaded revolver. Bobfather refuses to play and drops the gun, only for the weapon to discharge and shoot off Phoenix's toe. While Phoenix and her cult members all panic and search for the missing toe, her second-in-command, Beta, gives the ashes to the guys and lets them leave, having come to respect their traditional masculinity.
Meanwhile, having tortured Zane in a tanning bed, Jack gets their location and heads after them. Bobfather and Bender take two bicycles and ride to Backwater, where they get directions to Celia's house see that Shelly and Doc have also made it there after a ten-mile walk that involved having to eat a skunk. Celia reveals that she became pregnant by Durfy and now has an adult daughter, Jennifer, who strongly resembles her father. Jack is shocked and realizes that the ashes belong with Celia and Jennifer until they can all get together again and scatter them together. However, Bobfather's helicopter arrives, causing Jack to drop the urn and scattering the ashes anyway. Having bonded over the chaotic experience, the friends all reunite and leave in the helicopter.
