The film picks up immediately where the first film, Harold & Kumar Go to White Castle, left off, with Harold Lee (played by John Cho) and Kumar Patel (played by Kal Penn) boarding a plane to Amsterdam so that Harold can pursue his love interest, Maria, whom he met the previous night.
However, the flight doesn't go as planned, as Kumar is mistaken for a terrorist after he is caught trying to light a bong on the plane. The two are taken into custody by the Department of Homeland Security and sent to Guantanamo Bay, where they are interrogated by a ruthless agent named Ron Fox (played by Rob Corddry).
With the help of a fellow prisoner, a man named Colton (played by Eric Winter), Harold and Kumar manage to escape from Guantanamo Bay and set out on a series of misadventures as they try to clear their names and avoid being captured by the authorities. Along the way, they encounter a variety of colorful characters, including a racist hillbilly, a bottomless party, and Neil Patrick Harris playing a fictionalized version of himself.
The film is filled with raunchy humor and over-the-top antics, as Harold and Kumar navigate their way through a series of absurd situations. At its core, however, the film is about two friends who are willing to do whatever it takes to protect each other and stay true to their bond, even in the face of extreme adversity.