Unbeknownst to humans, a supermarket called Shopwell's is filled with anthropomorphic grocery items that believe that the human shoppers are gods, who take groceries they have purchased to a utopia known as the "Great Beyond". Among the groceries in the store is a sausage named Frank, who dreams of living in the Great Beyond with his hot dog bun girlfriend Brenda and his friends Carl and Barry.
Frank and Brenda's packages are purchased by a female shopper. On their way out of the store, a returned jar of honey mustard tries to warn the groceries that the Great Beyond is a lie, but nobody listens except Frank. Before committing suicide by falling onto the shop floor, Honey Mustard tells Frank to seek out a bottle of liquor named Firewater. Honey Mustard's suicide creates an accidental cart collision that causes Frank, Brenda and several groceries to fall out of the cart, including a Jewish bagel named Sammy Bagel Jr., a Muslim lavash named Kareem Abdul Lavash (who hate each other) and an aggressive douche who, after his nozzle is bent on impact, swears revenge on Frank and Brenda.
Seeking to verify Honey Mustard's warning, Frank leads Brenda, Sammy and Lavash to the store's liquor aisle. There, he meets Firewater, with whom he smokes marijuana from a kazoo and learns that Firewater and his colleagues, the Non-Perishables, created the white lie of the Great Beyond to assuage the inhabitants' fear of being eaten. Frank vows to reveal the truth and is encouraged to travel beyond the store's freezer section to find proof, while Brenda, Sammy and Lavash are brought by a bottle of tequila (who is revealed to be working for Douche) to the Mexican food aisle, until a lesbian taco named Teresa del Taco (who is in love with Brenda) helps them escape Douche.
Meanwhile at the shopper's house, Carl and Barry are horrified to witness the murder of other purchased groceries being cooked and eaten by her. Carl is sliced in half by the shopper, but Barry manages to escape and encounters a human drug addict who becomes able to communicate with his groceries, one of them being Gum, a wad of chewing gum resembling Stephen Hawking, after injecting himself with bath salts. However, the bath salts soon wear off and the addict prepares to cook Barry. The addict accidentally burns himself and Barry yanks his shoelaces, making him slip and causing an axe to fall and decapitate him.
Frank's friends disapprove of his skepticism of the Great Beyond. He discovers a cookbook beyond the freezer section and reveals its contents to the store's inhabitants. They panic at first, but then shortly refuse to believe Frank until Barry, Gum, and the other groceries from the addict's home return with the addict's severed head, proving that the humans can be killed. The group drugs the human shoppers and employees with toothpicks laced with bath salts, whereupon an epic battle begins. Several humans are gruesomely killed while Douche takes control of Darren, the store manager. He confronts Frank about becoming a god now that he is in control of Darren and takes a bite out of Frank's torso. Brenda saves Frank as Barry and the other groceries catch Douche and Darren in a pail strapped to propane tanks. They are then launched out of the store as the tanks explode, killing them both.
The inhabitants celebrate their victory with a massive orgy. Later, Frank and his friends visit Firewater, who had a psychedelic experience and discovered that their world is not real; they are merely cartoon characters voiced by famous actors in another dimension. Gum has constructed a portal to this dimension, and the group decide to travel there to confront their creators.
Michael Cera as Barry, a deformed sausage who is one of Frank's friends.
James Franco as a drug addict who is the first human to see food as sentient beings after injecting himself with bath salts.
Bill Hader as Firewater, an old Native American bottle of liquor and the leader of the Non-Perishables.
Hader also plays Tequila, a bottle of tequila who was a crony of Douche's as he led Brenda and her friends to be caught by him in exchange for his life, which backfired.
Salma Hayek as Teresa del Taco, a Mexican lesbian taco who has a crush on Brenda.
Jonah Hill as Carl, a sausage who is friends with Frank and Barry.
Anders Holm as Troy, a sausage who picks on Barry.
Nick Kroll as Douche, a foul-mouthed douche and Frank's archenemy who seeks revenge on Frank for accidentally breaking his nozzle and preventing him from reaching the "Great Beyond".
David Krumholtz as Kareem Abdul Lavash, a Middle Eastern lavash who has an on-and-off rivalry with Sammy Bagel Jr. He is implied to be Muslim as he desires “77 bottles of extra virgin olive oil”.
Danny McBride as a jar of honey mustard who is returned to his shelf upon the shopper mistaking him for regular mustard, and tries to warn Frank and the other products of the reality of the "Great Beyond" before committing suicide.
Edward Norton as Sammy Bagel Jr., a Jewish bagel who has an on-and-off rivalry with Lavash.
Craig Robinson as Mr. Grits, an African-American box of grits and a member of the Non-Perishables. He has a grudge against crackers (a pun on the pejorative term).
Seth Rogen as Frank, a sausage who sets out to discover and expose the truth about the "Great Beyond".
Paul Rudd as Darren, the manager of Shopwell's who is nicknamed the "Dark Lord" as he disposes of expired food and spilled items.
Kristen Wiig as Brenda, a hot dog bun who is Frank's love interest.