Dale Denton (Seth Rogen), cuyo trabajo es entregar citaciones legales, le compra la marihuana a un camello que se llama Saul (James Franco) porque le vende un nuevo tipo de hierba llamado “Pineapple Express”, en honor a un fenómeno atmosférico. Saul quiere hacerse amigo de Dale, pero éste sólo está interesado en los negocios. Casualmente, Dale es testigo de un asesinato cometido por una policía corrupta, Carol Butler (Rosie Perez), y por el líder de una banda, Ted Jones (Gary Cole). Por accidente se deja en la escena del crimen algo de la hierba de Saúl y ambos tienen que huir de la banda de criminales y de los agentes de la ley.

Lazy court-process clerk and stoner Dale Denton has only one reason to visit his equally lazy dealer Saul Silver: to purchase weed, specifically, a rare new strain called Pineapple Express. But when Dale becomes the only witness to a murder by a crooked cop and the city's most dangerous drug lord, he panics and dumps his roach of Pineapple Express at the scene. Dale now has another reason to visit Saul: to find out if the weed is so rare that it can be traced back to him--and it is. 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. All aboard the Pineapple Express.