Following their triumphant experience in the 21 Jump Street program, Schmidt (Jonah Hill) and Jenko (Channing Tatum) find themselves back on the streets, this time on the hunt for narcotics. However, their pursuit of a group of drug dealers, led by the elusive Ghost (Peter Stormare), ends in failure. As a result, Deputy Chief Hardy (Nick Offerman) assigns them back to the program, now relocated to 22 Jump Street under the command of Captain Dickson (Ice Cube). Their new mission is to go undercover as college students in order to track down the supplier of a drug known as "WHYPHY" (Work Hard Yes Play Hard Yes), which caused the death of a student named Cynthia.
Upon arriving on campus, Jenko swiftly connects with a couple of jocks, Zook and Rooster (played by Wyatt Russell and Jimmy Tatro, respectively), with Rooster becoming a prime suspect in their investigation. Meanwhile, Schmidt catches the attention of an art student named Maya (portrayed by Amber Stevens), by pretending to be interested in slam poetry. Their relationship becomes complicated when it’s revealed that Maya is actually the daughter of Captain Dickson, who greatly disapproves of their liaison. This further strains Schmidt as he feels increasingly sidelined when Jenko grows closer to the jocks, who persuade him to try out for the football team.
As their investigation stalls, the duo decides to consult Mr. Walters and Eric (played by Rob Riggle and Dave Franco) in jail for guidance. They get valuable insight about a distinctive tattoo on the dealer in the photograph that reads "BOOM!" linked to the drugs, leading them to believe they can track down the dealer by locating the tattoo. However, while hanging out with the jocks, Jenko sees the tattoo on Zook's arm, increasing the tension between him and Schmidt as the latter suspects Zook's involvement.
During a counseling session, the pair reassess their leads and deduce that Zook might not actually be the dealer but perhaps a buyer instead. They conclude that Cynthia was the supplier on campus, with drugs being secreted in library books checked out by her. Soon after, they stake out the library and spot Ghost on campus, but once again, he manages to escape.
As Jenko receives an offer for a football scholarship and grapples with his future in law enforcement, Schmidt tries to maintain focus on their mission. However, their cover is blown when Schmidt's identity as an undercover cop is revealed, resulting in his withdrawal from college. Determined to take down Ghost, Schmidt goes after him solo during Spring Break, but Jenko insists on joining him for one last operation together.
Their investigation leads them to a bar where Mercedes (played by Jillian Bell), identified as Ghost's daughter, gives orders to other drug dealers. They orchestrate an ambush, leading to an intense chase. After a series of skirmishes, Schmidt and Jenko manage to confront Ghost, leading to an explosive showdown that results in his demise. With the dust settled, the duo reconciles and discusses their future, with Dickson presenting yet another undercover mission at a med school.
In the amusing credits sequence, viewers are treated to a compilation of comedic moments from their undercover escapades. Finally, in a humorous post-credits scene, Mr. Walters and Eric share a cozy moment in prison, with a rather panicked Eric being informed about an unexpected situation.
