Cheech and Chong meet up by chance on the highway somewhere in California. They go in search of some dope and are accidentally deported to Mexico where in their desperation to get home they agree to drive a van back to the States so they can get back in time for a gig they are due to play. Unaware of the properties from which the van is constructed they make their way back having aquired a couple of female hitch-hikers whilst all the time avoiding the cops whom they are not even aware are following them.

Harold Lee and Kumar Patel are two stoners who end up getting the munchies. What they crave the most after seeing a TV advertisement, is a trip to White Castle. So from here, follows a journey for the burgers they require. On their way they will encounter many obstacles including a raccoon, a racist officer, and a horny Neil Patrick Harris.

Big city girl Caroline is new to a small town, she disregards her high school classmates, and then just for kicks starts a sexual relationship with her teacher, Mr. A. Meanwhile, there's a serial killer roaming the town, an industrial fire burning on the outskirts, and Thurston is mourning the loss of his best friend. As Thurston falls in love with Caroline, realities quickly catch up to all characters, and they are all going to have mature or face the consequences.