Schmidt and Jenko are back on the streets investigating narcotics trafficking two years after their triumph in the 21 Jump Street program. However, after failing to apprehend a gang of drug traffickers commanded by The Ghost, Deputy Chief Hardy reintroduces the duo to the undercover program, placing them under the command of Captain Dickson, who is now stationed across the street at 22 Jump Street.

Their mission is to pose as college students in order to track down the source of a synthetic drug known as "WHY-PHY" (Work Hard? Yes, why don't you try harder? Yes) that murdered a student who was photographed buying it from a dealer on campus. Jenko befriends a couple of jocks named Zook and Rooster in college, and they soon become the prime suspects in a murder. When Schmidt and Jenko can't figure out who the dealer is, they go to Mr. Walters and Eric in jail for help, and Walters points out a peculiar tattoo on the dealer's arm in the photo.

Jenko discovers that Rooster does not have the tattoo but sees it on Zook's arm when hanging out with Zook and Rooster. Schmidt and Jenko are invited to join a fraternity organized by the jocks, but Schmidt declines, escalating their rivalry when Jenko meets their requirements. They eventually discover Zook is not the dealer, but rather a regular customer. They eventually track down The Ghost and his guys on campus, but The Ghost manages to elude them once more. Schmidt learns that Jenko has been offered a football scholarship by Zook, but he is unsure about his future as a cop. Schmidt then exposes his true name and leaves the dorm, which enrages Maya.