In a supermarket called Shopwell's, the foods and other grocery items see the humans who buy them as gods who take them to "the great beyond" when they are purchased. A hot dog named Frank (Seth Rogen) has dreams of living in the great beyond with his hot dog bun girlfriend, Brenda (Kristin Wiig). Frank and Brenda's packages are chosen by a human to leave Shopwell's, but en route they are warned by a returned jar of honey mustard (Danny McBride) that the great beyond is not what they have been led to believe. An accident during their trip to the registers causes a collision that leads to Frank, Brenda, a lavash named Kareem (David Krumholtz), a bagel named Sammy (Edward Norton), and an aggressive douche (Nick Kroll) falling out of the shopping cart. Douche's nozzle is damaged, for which he blames Frank. After being discarded by Darren (Paul Rudd), the store manager, he swears revenge.

With the rest of the groceries purchased and taken to the great beyond, Frank, Brenda, and the others decide to journey back to their aisles, but in an attempt to verify the honey mustard's warning, Frank leads them to the liquor aisle to meet Firewater (Bill Hader), who is purportedly knowledgeable about the great beyond. They meet a lesbian taco named Teresa (Salma Hayek), who takes a lustful passion for Brenda, and manage to reach the liquor aisle before Douche escapes from the store's backroom dumpster. Frank learns from Firewater that in the great beyond, the "gods" actually eat the foods that are chosen. Firewater reveals that he invented the story of the great beyond to assuage the fears of the foods who once knew their fate when being purchased. Frank is doubtful, but a Twinkie encourages him to visit the store's freezer section to find proof.

Meanwhile, the rest of the groceries who were chosen discover the truth about the great beyond when many of them are killed, cooked, and eaten. A hot dog named Barry (Michael Cera) manages to escape and wanders into the outside world alone. He stumbles across a human junkie (James Franco) with a Shopwell's shopping bag. With visions of returning to Shopwell's, Barry stows away with the junkie and is taken to his house. After injecting himself with bath salts, the junkie becomes intoxicated and finds himself able to see Barry and the other groceries in his home "alive" and descends into a panic. The items realize they can communicate with the gods while the gods are under the influence of bath salts. After sobering up, the junkie believes this experience to have been a dream, and tosses Barry into a pot of boiling water. Barry survives, and an accident results in the junkie being decapitated.

Frank reunites with his friends and reveals that he deliberately led them to Firewater, as well as of his intentions to travel to the freezer to learn more about the gods and the great beyond. Brenda questions his motives and heads back to her aisle, while rejecting Teresa's advances due to the gods' rules that require her to only be with a hot dog. After reading a cookbook behind the freezer, Frank discovers the truth. He reveals the cookbook to the rest of Shopwell's, but everyone ignores him, fearing they will lose their sense of purpose. In rescuing Brenda from being purchased again, Frank is reunited with Barry, who has returned to Shopwell's with his new friends. Barry reveals that the gods can be killed and that they can be communicated with when they are high on bath salts. Frank gives an inspiring speech to the store and apologizes for not respecting the others' beliefs, giving them a sense of hope.

The foods then devise a plan to shoot the human shoppers with toothpicks laced with the bath salts so the humans will be able to see the foods for what they are. When the humans become high, a store-wide battle ensues. A vengeful Douche arrives and attacks Darren, taking control of him by inserting his nozzle into Darren's anus. The foods overpower him and kill all the humans. Finally free, all the foods in the store partake in a massive orgy in celebration. Later, they are informed by Gum, a Stephen Hawking–esque wad of chewing gum, that he and Firewater have discovered that they do not exist and are merely cartoon characters, manipulated by human animators and voiced by celebrities in another dimension. Gum reveals a portal that he made that will allow them to travel to this dimension, and the foods decide to go there to meet their creators.