In 1937, a military facility is on watch behind a two-way mirror as a soldier (Bill Hader), smoking marijuana, begins to reveal very graphically what he hates about the army, but still remains euphoric. A high-ranking officer (James Remar) immediately closes the project and deems marijuana illegal.
Jump ahead seventy years later, Dale Denton (Seth Rogen) is a 25-year-old process server and habitual marijuana smoker. He makes a visit to the home of his drug dealer, Saul Silver (James Franco), to buy marijuana. Saul tells him that he may already know the identity of Dale's next customer, Ted Jones (Gary Cole). Dale drives to Ted's house and witnesses Ted and a police officer, Officer Carol Brazier (Rosie Perez), shoot a man to death. Dale panics and flees the area, but leaves his roach at the scene, which contains a rare strain of marijuana called Pineapple Express. Ted is able to identify the strain and sends his two henchmen, Budlofsky and Matheson (Kevin Corrigan and Craig Robinson) to a dealer, Red (Danny McBride), who tells them that he has only sold the pot to Saul.
Dale flees to Saul's apartment and learns that Ted is a dangerous drug lord and could trace the roach back to Saul. Dale and Saul flee into the nearby woods while Ted's henchmen persuade Red to arrange a meeting with Saul. They accidentally fall asleep in Dale's car and wake up to find that they missed their meeting with Red. They leave the woods and arrive at Red's house, hoping to determine whether Ted has linked them with the Pineapple Express. Red says Ted isn't after them but Dale realizes that he's lying, and starts a fight that results in Red getting knocked out. They wake Red and question him until he reveals that Ted has discovered who they are and is going to kill them. Dale and Saul decide that they must leave the city.
In order to leave town, Dale and Saul sell some Pineapple Express to raise bus fare. However, a police officer named Barber (Cleo King) sees Dale and arrests him for selling marijuana. In the back of the cruiser, Dale tries to convince Barber that Brazier is corrupt and tells her that he witnessed her and Ted murder a man. Barber recognizes Brazier and promises him that she will investigate her soon. However, Saul leaps out in front of the police car and hijacks it thinking that Brazier is the one driving. Brazier hears a police radio call of Dale's arrest and pursues Dale and Saul in a high-speed chase but they manage to escape. After an argument with each other about the situation they are in, Dale and Saul go their separate ways. Saul visits his grandmother in an assisted living home but is kidnapped and held hostage in Ted's lair beneath a barn. Dale enlists Red to help him rescue Saul but Red unexpectedly backs out at the last minute and Dale is captured. While Dale and Saul are held hostage, they reconcile with each other and make plans to escape.
Suddenly, Asian mobsters attack the barn to avenge a fellow gangster's death at the hands of Ted and Officer Brazier (the same murder that Dale witnessed). Dale and Saul finally free themselves but are caught by Matheson. Matheson grazes Dale's ear with a gunshot but is disarmed and shot by Saul. Dale and Saul join the fight and a brawl ensues between Dale and Ted. When Budlofsky refuses to kill Saul, Matheson emerges from the lair and shoots him in the chest, killing him. He turns around to kill Saul but Red drives through the barn and saves Saul by hitting Matheson with his car. Red is then seemingly shot to death by Brazier. One of the mobsters activate a bomb, resulting in Ted's death, and setting fire to the barn. When Red's car explodes, it flips over and lands on Brazier, killing her. The explosion incapacitates Saul but Dale finds him and carries him out of the burning barn. Red, wounded but still alive, also escapes and reconciles with them. Afterwards they eat breakfast at a diner and talk about their adventure before Saul's grandmother picks them up and takes them to the hospital.
Who drives through the barn to save Saul?
Red