Lazy stoner and process server Dale Denton (Rogen) has only one reason to visit his equally lazy dealer Saul Silver (Franco): to purchase cannabis, specifically, a rare new strain called Pineapple Express that is hot on the drug market. Saul genuinely wants to befriend him, but the selfish Dale is only interested in gaining access to the weed. When he becomes the only witness to a murder by a crooked cop (Rosie Perez) and the city's most dangerous drug lord (Gary Cole), he panics and dumps his roach of Pineapple Express at the crime scene while fleeing.

Upon returning to his dealer, he finds out the weed is so rare that it can be traced back to him. Both decide to flee and forsake the idea of calling the police, because anyone could be involved with the murder. As Dale and Saul run for their lives, they quickly discover that they’re not suffering from weed-fueled paranoia; incredibly, the bad guys really are hot on their trail and trying to figure out the fastest way to kill them both. Further complicating things, Saul inadvertedly drags Dale's girlfriend Angie (Heard) into the mess.