Immediately following the events of Harold & Kumar Go to White Castle, Harold Lee and Kumar Patel fly to Amsterdam so Harold can pursue a budding romance with his neighbor. Upon arrival at the airport, Kumar creates trouble while going through security in order to get weed on the plane. Harold and Kumar board the plane, and mid-flight, an old woman sees Kumar lighting his new invention, a smokeless bong. Mistaking it for a bomb, she screams "Terrorist!", causing Kumar to drop the bong, which breaks and emits a visible 'gas,' prompting another passenger to scream "Poison Gas!". Air marshals detain the duo and the plane returns to Washington D.C., where Ron Fox, the neurotic Deputy Secretary of Homeland Security, sends them to the Guantanamo Bay detention camp, while there they meet a guard named Big Bob and are almost forced to eat his "cock meat sandwich" but are saved by two other terrorists. Eventually, they escape and sneak into Florida with the help of Cuban refugees. They go to see a friend of theirs, Raza, who is hosting a bottomless party and he encourages them to travel to Texas in search of Colton, with hopes that he will be able to help them through his father, who is connected with several high political officials. They borrow Raza's yellow convertible Ford Mustang, which they crash and abandon in Birmingham, Alabama, then after a few days in the woods, they encounter a brother and sister, who have an inbred son with one eye. After leaving that situation, they encounter the Ku Klux Klan where they manage to blend in temporarily, only to be caught by the two members who they were impersonating, who accuse them of being Mexicans.
After escaping the Klan, they get picked up by Neil Patrick Harris. Neil Patrick Harris starts eating hallucinogenic "magic" mushrooms while driving, and they soon come to a blockade where they all realize the FBI is looking for them. Harold and Kumar then cover themselves up with a blanket in the backseat, and Ron Fox walks up to the car. Once he realizes he's looking at Neil Patrick Harris, he tells him how much of a huge fan of his he is. Of course, Neil Patrick Harris at this point sees a unicorn with another version of himself riding outside the other window of his car... he seemingly ignores this and tries to act cool. After Ron finishes up talking to Neil, he drives off, still seeing the unicorn.
On the way to Texas, Neil decides to stop at a whorehouse, where he feels like he needs to get it on with one of the many whores that lie there within. Harold and Kumar reluctantly go inside with him, and the whores line up for business. Neil chooses his and goes into one of the rooms. Kumar chooses two whores and they go off to a separate room. Harold, feeling quite uncomfortable with the situation, sits outside in the lobby, talking to the other whores about the ordeal Kumar got him into, all in the meantime very stressed out, thinking Kumar is having the time of his life. However, flash over to Kumar's room, he's having the same breakdown with the hookers, confessing he's still in love with his ex-girlfriend Vanessa, who is marrying Colton. All of a sudden, the hooker that was with Neil Patrick Harris comes out of their room, screaming... Neil had branded his name on the bottom of her buttocks. As they're all running out, Neil trails behind them, and even though Harold and Kumar are in the car first, Neil Patrick Harris gets shot in the back multiple times with a shotgun by the whorehouse owner (Beverly D'Angelo), leaving him presumably dead. Harold and Kumar scream and drive off as the owner tries to shoot down their car. While driving, Harold looks through Neil Patrick Harris' stuff to see if there's any contact info for his parents or something, but all they find is the mask of Chris Fehn of Slipknot, a jar full of hair, and a whole bunch of cans of mace.