The film begins with an episode of the TV series "American Success Story" documenting the lives of the main characters since the last movie. Lou Dorchen (Rob Corddry) has become a mogul with his Lougle empire and his side band Motley Lou. Nick Webber (Craig Robinson) has become a popular musician mainly because he's made hit songs from the present before the actual artists could make it themselves. Lou's son Jacob (Clark Duke) hates his father and doesn't really want to be associated with him. Nick also mentions their buddy Adam Yates (John Cusack), who wrote a bestselling book and is currently going on a trip of self-discovery.
Nick is seen recording a music video for the song "Stay", which he ripped off of Lisa Loeb and incorporated his own lyrics. The real Lisa Loeb works as his cat wrangler and mentions that the song feels personal to her. Nick quietly apologizes for stealing the song.
Lou joins his employees in the board room with his employees, all of whom are sick of his man-child schtick. One of the employees, Brad (Kumail Nanjiani), points out that the company is going down hard, but Lou doesn't care. He brags about going making his success through time travel, while Brad retreats to the lab to find a way to save the company.
Lou hosts a big party that night in his mansion. He makes Jacob act as a butler. Jacob spots the pretty coat-check girl, Sophie (Bianca Haase), and tries to talk to her, yet she thinks he really is just a butler. At the bar, Nick and Lou are approached by an old schoolmate, Gary Winkle (Jason Jones), who is a total loser. He tries to convince Lou to buy a piece of land from him, which Lou declines. Nick also upsets his wife Courtney (Kellee Stewart) since she wanted to go to her sister's home, but Nick always makes her go wherever he wants.
Moments later, Lou goes up the stairs and makes a big speech where he tells everyone to do things for themselves and to forget everyone else, to everyone's dismay, including Lou's wife Kelly (Collette Wolfe). The lights go out, and a gunshot rings out. Somebody has shot Lou in the dick. He tumbles down the stairs bleeding profusely. Nick and Jacob grab him and pull him up the stairs. Jacob pulls a switch shaped like a squirrel, taking the guys to the deck outside to reveal the hot tub time machine. Jacob grabs a vial of nitrotrinadium and puts it in the hot tub, setting it to send them back to stop Lou's killer. Jacob also happens to spot Adam's trench coat lying by the tub. They also get blackout drunk to set the mood properly.
When the guys wake up, Nick and Jacob find Lou unconscious. They think he's dead, until he farts and yells that his dick is still in place. They enter the home to find it looking a lot more lavish and clean. They look up and see a portrait of Jacob, older and more bald. Sophie enters the room topless and kisses Jacob. The guys deduce this is now Jacob's place, and that they've jumped ten years into the future. They look in the mirror and see their older selves. They run back to the hot tub, only to find that there is no more nitro left. The hot tub repairman (Chevy Chase) then shows up out of nowhere to explain that they are stuck there without nitro. Jacob then figures out that they must be in an alternate timeline, and that Lou's killer must be from the future.
The guys walk the streets to see that not a lot has changed in the future (besides the dog behind them riding a hoverboard). They sit down and briefly mention how Adam would be there to solve the problem. Jacob brings up seeing Adam's coat at the party, leading Lou to think that Adam tried to kill him.
The three go to Adam's home to find another man living there. His name is Adam Yates-Steadmeyer (Adam Scott), the son of Adam and his old girlfriend Jenny. Adam Jr. is excited to see Nick and Jacob, but he has no idea who Lou is. The guys explain their relation to him and their situation. They meet Adam Jr.'s fiance Jill (Gillian Jacobs). She and Adam Jr. are both fans of Nick and his "Webber Strut" (something Nick came up with to apologize for ripping off other artists) and she offhandedly mentions to Nick that he's fallen on hard times, something he isn't aware of.
The guys, joined by Adam Jr., continue their mission, when Adam Jr. summons a smart car that runs on emotions. Lou behaves rudely around it, causing the smart car to secretly plot to kill Lou.
Lou spots a building with Gary's face on it, making him think he tried to kill him and steal his success. He runs in the building and tackles Gary, but Gary explains that Lou not buying the land from him actually helped him turn a profit. He invites the guys to his nightclub, where he tells Nick he's sorry to hear about him and Courtney, something else that Nick isn't aware of. Lou does cocaine while Adam Jr. requests the strongest thing in the place. Gary gives him a new drug called "the electric ladybug". He has the shot girl stick it on Adam Jr.'s neck, and he advises him not to take it off for 24 hours. Adam Jr. then experiences an intense high throughout the night. At one point he calls Jill and tells her he's a god.
The guys are picked up the next day to go to a popular game show, Choozy Doozy, with Nick as the special guest. Adam Jr. calls Jill again and states that the experience from the previous night led him to realize that most of what he's said and done through his life is a life, to her shock. The host (Christian Slater) tells the audience to pick something for Nick to do. After three other choices, Lou yells "FUCK A DUDE!" Naturally, that's what the audience chooses, but since Lou "choosed" it, he must "dooze" it. He and Nick are put in a virtual reality simulator where they are forced to have sex or get shocked by 10,000 volts of electricity. Lou chooses a lifeline and makes Adam Jr. take his place, something that Jill watches on TV.
Following this experience, Jacob tells Lou that he's a virus that only causes misery everywhere he goes. He leaves to go back to Gary's club. Lou then takes off the ladybug from Adam Jr.'s neck, causing him to have a seizure. They take him to the hospital where Kelly is now a nurse, and she divorced Lou after getting clean. She gives Adam Jr. some nanobots to fight the narcotics, but they don't work with the ladybug and instead make his balls inflate. Kelly gets a needle and sticks it there to remove the fluid, squirting some all over Nick and Lou's faces.
Back at the nightclub, Jacob orders every drug and drink he can get his hands on. Sophie comes in, disgusted with Jacob's antics, saying he's just like his father, a realization that hits Jacob hard. The guys return to find him, when Gary says Jacob "went to see the family therapist." Lou knows what this means, and he finds Jacob on the roof of his home. Lou goes up to talk him down and admits that the men in their family are screw-ups, but there's still hope for Jacob. They hug for the first time. Jacob accidentally slips off the roof, and Lou tries to save him. Their hands slip, but Jacob is saved by a suicide prevention system that he apparently invented.
The guys see a news report on Brad, who has invented the nitro in the future. Adam Jr. realizes Brad will be at his wedding, which is that day. The guys rush to the chapel to find Brad while Adam Jr. goes on to get married. Jill is too mad at him from what he's said and done on TV. She gets wasted and spots Lou. The two of them have sex, which Adam Jr. unfortunately walks in on.
Meanwhile, Jacob finds Brad and deduces that he's not the killer since he went on to find his own success away from Lou, and thus had no need to kill him. This doesn't stop Lou from punching Brad. The guys then learn that Adam Jr. stole the nitro and went back to the past, meaning HE is the killer, and it's Lou's own fault that he gets shot for having sex with Jill.
The guys run outside to find the smart car attempting to kill Lou. He sincerely apologizes to it, and it takes the guys to the mansion. However, Adam Jr. already went back in time, taking the nitro with him. As the guys sit in hopelessness, Jacob realizes that with the nitro in the past, it must now be in the future. He opens the chamber to find many nitro vials. He puts one into the hot tub and gets them back to 2015.
The guys walk in on the party the moment that Lou is going to give his speech. Lou is slightly more sincere this time around, but he and the guys spot Adam Jr. pick up a shotgun and attempt to shoot Lou in the dick. Lou talks him down and apologizes for what he's done, saying he'll blast himself. Adam Jr. is sorry and he pulls the gun away from Lou, accidentally shooting a portrait of Lou having sex with a tiger.
Following this, Nick apologizes to Courtney and says he just wants to spend time with her. Lou tells Kelly he wants to get clean, and asks her to join him for a 12-step program, which she agrees to. Jacob approaches Sophie and convinces her to join him in a relationship, promising her it will be a crazy experience that will be worth it. She smiles and they kiss.
The guys go outside to the hot tub once again. As Lou reflects on the adventure, a whirlpool rises behind him, and his head gets blasted off. Emerging from the whirlpool is... Patriot Lou! He tells the other three that this Lou was terrible and he needed to die. He invites the guys to join him in "making America happen." Against their better judgment, Nick, Jacob, and Adam Jr. follow Patriot Lou for another dip in the hot tub time machine.
During the closing credits, we see the guys exploit the time machine to change history. Adam Jr. saves Lincoln from getting assassinated and even becomes the first man to land on the moon (which he says is just a sound studio in New Mexico). Jacob has sex with Marilyn Monroe. The guys discuss time travel with Einstein. They even end up becoming The Beatles, which upsets Lou since he turned out to be Ringo.