Investment banker Harold Lee is persuaded by his colleagues Billy and JD to do their work while they leave for the weekend. Kumar Patel attends a medical school interview, but intentionally botches it to prevent getting accepted. Harold meets his neighbor Maria, but is unable to admit his feelings. After smoking marijuana with Kumar, and seeing an advertisement for White Castle, the pair decide to get hamburgers. After traveling to the nearest White Castle in New Brunswick, they find it replaced by "Burger Shack" but are informed by an employee of another White Castle in Cherry Hill.
When Kumar becomes sober, he suggests stopping at Princeton University to buy more marijuana. Kumar buys marijuana from a student named Bradley and after smoking more marijuana, they are discovered by campus security and forced to flee, losing their marijuana. The guards discover Bradley's bag of marijuana and arrest him. Harold and Kumar resume their drive, and Kumar pulls over to urinate. A raccoon gets in the car and bites Harold. Kumar takes Harold to a hospital where Kumar's father and older brother work. Kumar steals ID badges to obtain medical marijuana, but after being mistaken for his brother, Kumar performs surgery on a gunshot victim and after a successful surgery the patient tells them how to reach White Castle.
On the road, Kumar spots Maria. He decides to get her attention so Harold can talk to her, but Harold panics and presses the accelerator, causing the car to crash into a ditch. They are rescued by Freakshow, a tow-truck driver, who takes them to his house to repair their car and gives them permission to have sex with his wife. Harold and Kumar are propositioned by Freakshow's wife, but after Freakshow suggests a foursome, Harold and Kumar flee in disgust. Kumar pick up a hitchhiker, Neil Patrick Harris, who is high on ecstasy. Harold and Kumar go into a convenience store to get directions and Harris drives away. The duo are then harassed by a racist police officer for jaywalking. Harold attempts to punch Kumar for teasing the officer, but ends up punching the officer.
In jail, Harold sees Bradley being released and his stash confiscated. Kumar fakes a 911 call to draw the police away and breaks into the station to free Harold. Harold and Kumar flee with Bradley's stash. The pair encounters an escaped cheetah, and after smoking marijuana with it, they ride it. They realize the cheetah took them in the wrong direction and consider returning home, but when Harold and Kumar see their Jewish neighbors Goldstein and Rosenberg eating at a hot dog restaurant, Harold wants the satisfaction from achieving their goal. After encountering a group of sport punks who harass the pair, Harold and Kumar steal their truck. A police officer spots the speeding truck and chases them. They are trapped when they reach the edge of a cliff. Spotting the White Castle below, Harold and Kumar use a hang glider from the truck to reach their destination. The pair place their orders but are disheartened to find they have no money. Harris suddenly appears, and pays for their meal as an apology for stealing and then trashing their car.
Kumar realizes he wants to be a doctor, but is afraid of conforming to the stereotype of Indians becoming doctors. Harold notices his co-workers pull up with two women and gets angry because they said they had to work with clients, when they were out partying. He confronts them for leaving their work to him, and threatens to get them fired if it happens again. After returning to their apartment they encounter Maria in the elevator. Harold professes his feelings for her and they kiss. She informs Harold that she is leaving for Amsterdam but will return in ten days. Kumar convinces Harold to go with him to Amsterdam to pursue Maria, reminding him that marijuana is legal in the Netherlands.
Who is arrested by campus security?
Bradley