Following the events of Harold & Kumar Go to White Castle, Harold Lee and Kumar Patel purchase plane tickets to Amsterdam so Harold can pursue a romance with neighbor Maria. Before boarding their plane, they encounter a friend from college named Colton, and Kumar’s ex-girlfriend, Vanessa, who are getting married in Texas. During the flight, a woman suspects Kumar is a terrorist after mistaking his bong for a bomb. Sky marshals detain them and the plane diverts to Washington D.C. Ron Fox, an obsessive and racist Deputy Secretary of Homeland Security, sends them to Guantanamo Bay detention camp in Cuba, thinking they are agents of a joint Al-Qaeda and North Korean conspiracy, against the advice of NSA Vice-Chairman John Beecher. With the inadvertent assistance of two other prisoners, Harold and Kumar escape and board a Cuban refugee boat to Miami, Florida. They meet with their college friend, Raza, who loans them a car so they can travel to Texas to get help from Colton, whose family has political connections.
During the car ride, Kumar remembers meeting Vanessa at the library and smoking a joint for the first time. Fox interrogates Harold and Kumar’s parents utilizing an incompetent interpreter, despite their English fluency. Harold and Kumar crash their car in Birmingham, Alabama. They flee on foot after mistaking an approaching group of helpful African-Americans for gang members. They meet a friendly hunter and stay with him and his wife at their well-kept trailer home. When someone knocks at the door, Harold and Kumar hide in the basement and discover the couple’s inbred cycloptic son. At night, while Kumar dreams of a threesome with Vanessa and a large bag of marijuana, Harold is shocked to find the son in his bed, and they promptly leave. In the woods, Harold and Kumar encounter a Ku Klux Klan rally. They hide until some members arrive with a beer keg. After knocking them out, and putting on their robes, they mingle until the other two return, declaring them to be “Mexicans”. The Klansmen chase Harold and Kumar until their leader accidentally sets himself on fire. The two run into Neil Patrick Harris, who offers them a ride.
Fox interrogates the African-Americans Harold and Kumar encountered in Birmingham, as well as Harold and Kumar’s Jewish friends, Rosenberg and Goldstein. Under the influence of psychedelic mushrooms, Harris smuggles Harold and Kumar past Fox’s security checkpoint. They stop at a brothel, but while Harris leaves with a big-breasted prostitute, Harold and Kumar talk about their friendship issues with their girls. Harris causes a situation by branding his woman. As they flee, Harris is shot in the back. While grieving, Harold and Kumar look through Harris’ possessions, finding Chris Fehn’s mask, a jar of human hair, and a dozen mace cans. Harold and Kumar arrive in Texas, where Colton promises to help them out of their situation, but when he sees Kumar reconnecting with Vanessa, he turns them over to Fox. On a flight to Guantanamo Bay, Kumar apologizes to Harold for getting them into this situation and they forgive each other.
Harold uses Harris’ mace to incapacitate two guards, but Fox catches them. As he prepares to shoot them, an infuriated Beecher knocks down Fox and calls him out on his incompetence. He tries to tie Fox up but slips and knocks the plane door open, falling to his death. Everyone is sucked out the plane, and Kumar hangs on to Harold, who deploys a parachute. Fox tries to shoot them, but falls to his death, and they crash through the roof of President George W. Bush’s Texas house. Bush brings them to his recreation room, and they bond by smoking weed. Bush promises to pardon Harold and Kumar and to help them with whatever they need. Escorted by the Secret Service, Harold and Kumar interrupt Colton and Vanessa’s wedding. Colton confronts Kumar, but Harold punches him, and Kumar reconnects with Vanessa by reciting a poem he was writing when they first met. The three head to Amsterdam where Harold reunites with Maria, and they tour Amsterdam.