In 1937, within a military installation, a soldier (played by Bill Hader) is being closely monitored through a two-way mirror, where he openly shares his grievances about army life while enjoying marijuana. Due to his revelations, a high-ranking officer decides to terminate the project and makes marijuana illegal.
Fast forward to 2007, where we meet Dale Denton (Seth Rogen), a subpoena server. He pays a visit to his drug dealer, Saul Silver (James Franco), to purchase marijuana. Saul introduces Dale to the Pineapple Express, a unique strain that has just emerged in the market. During their conversation, Saul reveals that he might know Dale's next client, Ted Jones (played by Gary Cole), who is a figure linked to the drug trade as Saul gets his supply from Red, who, in turn, buys it from Ted.
While waiting outside Ted's residence to finish his joint, Dale witnesses a shocking event unfold—a police officer, Carol Brazier (played by Rosie Perez), alongside Ted, shoots a man in cold blood. In a panic, Dale leaves behind his half-smoked joint containing the distinctive Pineapple Express strain. When Ted discovers the roach, his henchmen, Budlofsky (played by Kevin Corrigan) and Matheson (portrayed by Craig Robinson), set out to find Red to get information about Saul.
Dale rushes back to Saul's apartment, where he learns the dangerous truth about Ted being a drug lord who can easily trace the roach back to them. They visit Red, who has already informed Budlofsky about their identities, putting them in grave danger. After a narrow escape, they realize Ted is intent on eliminating them for their involvement.
Dale decides to join his girlfriend Angie (played by Amber Heard) for dinner at her parents' place, but tensions escalate quickly as Dale arrives in a disheveled state and ends up having to convince Angie's father to lower his shotgun. Meanwhile, a power struggle brews as Ted, alongside Carol, consults Cheung (played by Dana Lee), the Asian mob boss, leading to serious threats and a promise of retaliation.
With stakes raised, Dale and Saul attempt to flee the city. They sell their Pineapple Express stash for bus fare; however, disaster strikes when Dale is arrested by Officer Bobbra (Cleo King). Despite expressing his intent to report the murders he witnessed, Saul impulsively hijacks the police car pursuing them.
After a heated argument causes a rift between them, Saul is captured, leaving Dale desperate to rescue him. Enlisting Red's help, they prepare for a showdown at the military facility where Saul is being held. In a twist of fate, their plan takes a turn when they find themselves amidst a chaotic brawl, with Asian gangsters seeking revenge.
In the ensuing chaos, both Dale and Saul manage to escape their ordeal but not without confronting their captors. The climactic clash culminates in a series of dramatic events, including Red driving through the barn to save Saul but getting shot himself. The tension peaks as a bomb detonates, leading to a fiery explosion that takes out not just Ted but also Carol.
In the end, Dale carries Saul away from the flames, where they are joined by the wounded but still alive Red. Their harrowing journey concludes with camaraderie over breakfast as they recount their wild adventure before being whisked away to safety by Saul's grandmother, ready for the next chapter of their lives.
