Dale Denton (SETH ROGEN) is a thirty-something process server who delivers subpoenas and such to all sorts of people, but most of all enjoys getting high when not hanging out with his high school aged girlfriend, Angie (AMBER HEARD). Accordingly, he often visits his drug dealer, Saul Silver (JAMES FRANCO), for his latest round of marijuana.
Saul's habitually stoned and thus not always quite there mentally, but he wants to be friends with Dale and thus lets him try a super strong variety of weed known as Pineapple Express. Dale agrees it's good, thanks him for that and his regular stash, and heads out for his next job.
It's then that he witnesses Ted Jones (GARY COLE), who turns out to be a huge drug kingpin, and crooked cop Carol (ROSIE PEREZ) murder a man. Dale panics, ends up making too much noise fleeing the scene, and drops his joint. The latter turns out to be a bad move since Ted immediately identifies the variety as Pineapple Express, which is unique to him. Dale has figured that out as well, and thus takes Saul with him to meet the latter's pot supplier, Red (DANNY R. McBRIDE), a two-bit weasel who will do or say anything to save his own hide.
When Ted's goons Budlofsky (KEVIN CORRIGAN) and Matheson (CRAIG ROBINSON) come knocking, Red immediately fingers Dale and Saul. With Ted then believing that Dale is some sort of hitman working for his Asian drug rivals, he puts the pressure on his goons to eradicate his problem. From that point on, Dale and Saul try to figure out what to do, a decision clouded by one or both of them often being high.