Harold (JOHN CHO) is a junior analyst at an investment banking firm who always has work dumped on him by his coworkers since they believe that Asians love crunching numbers. He also has a hard time telling the girl of his dreams, neighbor Maria (PAULA GARCÉS), how he really feels about her.
Kumar (KAL PENN) is applying to medical school, but only to please his dad, and he makes no attempt to impress a dean of admissions (FRED WILLARD) who can't believe the young man's disrespect and gall.
The two guys are best friends and roommates who decide that what they need this particular night is to get high, much like their neighbors Goldstein (DAVID KRUMHOLTZ) and Rosenberg (EDDIE KAYE THOMAS). Naturally, they then get a case of the munchies that's only exacerbated by a TV commercial for the White Castle burger joint. Harold & Kumar then set out on what's supposed to be a quick run for mini-burgers, not anticipating the various complications that will unexpectedly develop.
After learning that the local White Castle is closed, they embark on a much longer quest that involves running into actor Neil Patrick Harris (NEIL PATRICK HARRIS) who's high on ecstasy; several men who come on to Kumar including a male nurse (RYAN REYNOLDS); and Freakshow (CHRISTOPHER MELONI), a tow truck driver who says they can have sex with his wife.
As the night wears on and they have other run-ins with racist jerks and similar cops, nerdy drug dealers and more, the two become ever more determined to make it to the burger joint and satiate their pot-induced appetite.