The film starts with a "Previously on 21 Jump Street" opening, featuring a brief recap of the last film in which Officers Schmidt (Jonah Hill) and Jenko (Channing Tatum) were partnered up and became friends after they took down the drug dealers Mr. Walters (Rob Riggle) and Eric Molson (Dave Franco), up to Captain Dickson (Ice Cube) assigning them their newest assignment - going to college.
Schmidt bemoans the fact that he and Jenko are taking online courses instead of actually being there. They then head to Metro City Port to take on an assignment. There, they find the wanted drug lord, The Ghost (Peter Stormare), a man who is said to have made connections with the Mexican cartel. Schmidt dresses up as a cholo and gets in character to infiltrate the gang, but Jenko knows he sucks at improvising. The two meet Ghost and his men in a warehouse, where Schmidt plays up his role while Jenko is unconvincing. Ghost lets them into his truck to check out his supply. The two open a crate and an octopus jumps on Schmidt's face, inking in his mouth. In their panic, the two drop their accents and are found out. Ghost and his men shoot at Schmidt and Jenko and make their escape in the truck. Jenko hops on top of the truck to catch the goons, while a nervous Schmidt tries to climb over. His foot gets caught in a net and he falls, dangling over the edge of the truck. Jenko walks to the front and breaks the windshield, nearly arresting Ghost, until Schmidt gets on top of the truck and hits a beam, getting himself and Jenko caught with the net onto the beam, letting Ghost and his men get away.
The guys meet with Chief Hardy (Nick Offerman) over their latest screw-up. Hardy suggests that this wouldn't have happened if they just did the undercover Jump Street program again like last time. He adds that even though nobody had faith in their reboot, the guys got lucky, and now they have double the budget to move ahead with a new assignment (an obvious meta joke to the sequel). The guys are sent to the Vietnamese church across the street since the Koreans bought back the church on 21 Jump Street, and so they must now report to 22 Jump Street. There, the guys are impressed by the high quality look to the headquarters and see that Jenko's nerd friends from high school are now interns. They report to Dickson, who tells them they're going to MC State to investigate the appearance of a new drug called WhyPhy (stands for "Word Hard? Yes. Play Hard? Yes."). The guys receive a file on a victim of the drug, Cynthia Watson. She was high on WhyPhy and fell out her window to her death. They are also given a picture of Cynthia exchanging the drug with an unknown suspect.
Schmidt and Jenko make it to MC State, once again under their aliases of Brad and Doug McQuaid, and get adjusted to their dorm and returning to college life. They meet the Yang Twins, Keith and Kenny (The Lucas Brothers), who have a very interesting twin connection. The guys then head to some classes to try and find any possible dealers. Schmidt takes a psychology class and is immediately thought to be a narc. Jenko takes a history class taught by a professor (Patton Oswalt) that presses Jenko to question his lectures, since that's what he thinks college is all about in order for someone to find themselves. The professor also admits to sleeping with two students. The guys later go to an open mic night for slam poetry where Schmidt meets a pretty girl from his class named Maya (Amber Stevens). He goes up on stage to do a weird poem in honor of Cynthia, which gets a few laughs.
With no leads, Schmidt and Jenko realize they need to consult an expert. They go to prison to visit Mr. Walters, who brags about having a vagina and being Eric's bitch (the latter denies it and begs the guys to get him out). Walters takes a look at the picture of Cynthia and the suspect, and he mocks the guys for not looking at the picture closely to see that the suspect has a tattoo on his arm of a bazooka with "BOOM" written in a cloud. The guys visit a tattoo parlor and ask the tattoo artist if he remembers giving that tattoo to anybody, and he thinks he gave it to a football player with a red mohawk. Jenko recognizes the description to match a guy from his history class named Rooster (Jimmy Tatro).
The guys try out for the football team. Jenko immediately strikes up a friendship with another player named Zook (Wyatt Russell). Both Schmidt and Jenko try to keep an eye on Rooster and get a look at his arm to find the tattoo. Jenko shows impressive skills on the field, catching the attention of the coach (H. Jon Benjamin). Zook invites Jenko to a party at his frat house later that night, with Schmidt tagging along despite Jenko telling him he should stay behind. Jenko gets in with the frat guys, while Schmidt gets too close to Rooster in trying to find the tattoo and is sent away. While Jenko parties with Zook and the other frat boys, Schmidt runs into Maya and hangs out with her at the art building. He ends up sleeping with her in her dorm room. Meanwhile, Jenko joins Zook and Rooster on the football field where Jenko finally gets a look at Rooster's arm. He DOES have a tattoo, but it's of Rooster's high school football team, called the Red Herrings (get it?). Turns out that Zook has a tattoo on his arm as well - a bazooka with "BOOM" written next to it.
Schmidt wakes up and meets Maya's rude roommate Mercedes (Jillian Bell). She mocks Schmidt for looking old and for the way his sex with Maya sounded. She leaves and Maya tells Schmidt that Mercedes was Cynthia's roommate, and that Maya let her stay with her because she felt bad, even though she hates Mercedes. Schmidt then joins up with Jenko at the headquarters to report to Dickson, still with no leads, though Schmidt brags about having sex to Dickson, who gives him daps to show approval.
The guys meet up in their dorm, where they're eating blondies. The Yang Twins inform them that those are laced with WhyPhy. Later that night, the guys sneak out at night and infiltrate Zook's frat house as they are going over who they would like to recruit for their frat. As they listen in on the frat, they hear a great approval for Jenko to join, but no love for Schmidt. Zook thinks they should let him in since he's always with Jenko, but Rooster thinks he'll jeopardize whatever they have going on. Schmidt knocks over a mannequin and makes a loud noise, forcing him and Jenko to run before Zook finds them. The guys make it to their dorm but are caught by Zook and his guys, and then are stuffed in a trunk. There, they begin to feel the effects of the WhyPhy and start to trip out heavily. Schmidt experiences a dark and unpleasant trip while Jenko has a colorful and happy high. When they're pulled out of the trunk, they find that Zook and the other frat boys are merely hazing them for initiation. They subject Schmidt and Jenko to drinking games. Jenko excels and impresses the boys while Schmidt is uncomfortable and clumsy. When the last task involves pigs (and possibly pig shit), Schmidt walks out. Jenko follows and tries to convince him to stick around and have fun, but Schmidt wants no part of it. Jenko eventually starts spending more time with Zook while Schmidt is left alone.
Schmidt receives an unwelcome surprise from his parents as they visit him for Parents Weekend, not realizing he's undercover again. They meet Maya, and Schmidt's mom embarrasses him again. It gets worse when Schmidt finds out that Maya's dad is Dickson. They sit down to eat with Schmidt's parents and Maya's mom (Queen Latifah), which gets awkward after Dickson realizes that Schmidt slept with his daughter. He angrily throws food from the tables and makes a scene.
Maya is angry at her dad for being too controlling, so while she starts to hook up with Schmidt again, he decides they can just talk. They chat about Schmidt's high school experience (the undercover one) At the same time, Jenko is working out with Zook, trying to get him to spill details on Cynthia and WhyPhy. Zook appears dodgy and insists that he knows what he's doing. After talking to Maya, Mercedes shows up again and tells Schmidt that Cynthia got some sort of medication from the psychology professor, Dr. Murphy (Marc Evan Jackson).
Schmidt and Jenko sneak into Murphy's office to find something, but Murphy walks in and thinks they are there for a counseling session, mistaking the two for a gay couple. The guys sit down for the session, spilling their feelings toward each other, like Jenko feeling that Schmidt is too clingy and Schmidt feeling that Jenko is never listening to him. Murphy mentions something about embedding, in which details and such are glossed over and ignored or misinterpreted, leading the two to realize that perhaps Zook is not the dealer in the photograph, but that he is instead buying from Cynthia. They also deduce that she and the other dealers were hiding the WhyPhy in the library books since nobody goes there and would not bother to check them out.
The guys report to Dickson again, who is still pissed at Schmidt for sleeping with Maya. When Jenko deduces that fact, he goes wild and runs around headquarters laughing and telling everybody "SCHMIDT FUCKED THE CAPTAIN'S DAUGHTER!" Dickson gets back at Schmidt by tasing him in the balls. He adds that they have no more money in their budget.
Schmidt goes to the library to investigate while Jenko heads to the field for a football game. In the library, Schmidt sees Ghost and his goons waiting for someone. Schmidt texts Jenko to come by, persistently sending messages after messages until Jenko leaves the game to join him. They make enough noise to attract one of Ghost's goons to come over. Jenko pretends to give Schmidt a blowjob to draw attention away from themselves, but Jenko gets angry when the goon calls them "faggots". Jenko headbutts him, and Ghost recognizes him and Schmidt as cops. They take out their guns and begin shooting, forcing the guys to run. They run out to the campus where Jenko gets a helmet-shaped car. Ghost and his goons chase them in a hummer. They go all across the campus, causing an insane amount of property damage. During the chase, Jenko tells Schmidt that he got a scholarship to play football at MC State and that Zook invited him to be his roommate. They drive onto the football field, and the brakes are out. They both jump out of the car where it crashes and explodes onto the goal post. Schmidt is taken into custody for questioning, but not before letting Jenko stay behind so he can take the fall for him. He leaves campus, and Maya is mad at Schmidt for lying to her.
Jenko keeps hanging out with Zook and the other college kids while Schmidt goes back to park duty. Dr. Murphy is arrested after traces of WhyPhy were found in his office. Hardy declares the case closed. However, Schmidt looks into the case file to dig deeper. He and Jenko meet up in the park. Schmidt learns that Ghost has been paying for a student's tuition, while Jenko informs him that a large supply of WhyPhy is headed for Puerto Mexico for spring break. They decide to team up again and head down there to finish the job themselves.
The guys make it to Puerto Mexico and come to a big party on the beach. WhyPhy is being sold everywhere, and they find the person taking all the money - Mercedes. They follow her to a warehouse where they discover that she is Ghost's daughter, and they are organizing a network to distribute WhyPhy across the country. Even the Yang Twins are in on it. When Mercedes sees that they are both high on the drug, she almost kills them until Schmidt and Jenko try to arrest them. They are outnumbered by all the goons, so Dickson and the rest of the Jump Street division come in after following Schmidt's tracking device. As everyone opens fire, Ghost grabs Mercedes' bag with the money and runs. Dickson runs after him, but sees Maya in the warehouse partying with others. He stops to tell her that the girl always gets kidnapped during these climactic chases, only to have the tables turned when Mercedes shoots him in the foot and abducts him. Schmidt and Jenko split up so that Schmidt takes a Lamborghini (which upsets Jenko since he spent the whole movie wanting to drive a Lambo), while Jenko chases after Ghost. He manages to fight off his goons on the beach, using a stoned girl as a weapon.
Schmidt awkwardly drives the Lambo to a hotel where he catches up with Mercedes. They have an uncomfortable fistfight in a room where Mercedes keeps trying to kiss Schmidt, even though she continuously denies trying to do that. She knocks him off her and runs for it until Schmidt catches up to her. Dickson, having made it out of Mercedes' car, aims his gun at Mercedes, but she holds Schmidt at gunpoint. She is taken down by Maya, who whacks her over the head with a metal fish. Dickson and Maya arrest Mercedes, leaving Schmidt to join Jenko in catching Ghost.
The guys meet up and find Ghost trying to escape in a helicopter. A goon shoots at them, with Schmidt trying to take a bullet for Jenko (as he did in the last movie), only for him to jump too early, so Jenko gets hit in his arm again. Jenko kills the goon and makes it to the helicopter as it takes off. Jenko jumps off the roof and grabs onto the helicopter, with Schmidt successfully making the leap as well. As they fly over the beach, Jenko slips and Schmidt catches him. He orders Jenko to reach into Schmidt's shorts to grab a grenade. They slip and fall from the helicopter, but Jenko manages to throw it into the helicopter, destroying it and the whole supply of WhyPhy (Ghost is later revealed to have survived the explosion). As the two land in the ocean, they are applauded by the whole crowd, including Rooster and Zook.
Dickson congratulates the guys for fixing their screw-up, and then tells them their next assignment - medical school. This carries into the credits, as Dickson keeps assigning them to new schools, which pave the way for a bunch of fake "Jump Street" sequels, taking them places such as culinary school and a flight academy, with cameos from Bill Hader, Anna Faris, Richard Grieco (reprising his original "Jump Street" role as Booker), and even Seth Rogen as a temporary replacement for Schmidt. It goes further when it spawns fake merchandise such as a video game, action figures, and an animated series, ending with badass car chases and explosions.
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