The wedding of Will Turner and Elizabeth Swann is interrupted by Lord Cutler Beckett of the East India Trading Company, who has arrest warrants for the couple as well as for Commodore James Norrington, for allowing Captain Jack Sparrow to escape execution. Norrington's whereabouts are uncertain, as he resigned after his obsessive pursuit of Sparrow resulted in the Navy's flagship, HMS Dauntless, being destroyed in a typhoon. Elizabeth is imprisoned and Jack reunites with Will’s father Bootstrap Bill, on the Black Pearl. Bootstrap reveals he is a crewman on the Flying Dutchman, captained by Davy Jones, whom Jack previously made a deal with to raise the Pearl from the depths. Jack must join Jones' crew or be dragged to Davy Jones' Locker by the monstrous Kraken. Beckett promises to free Elizabeth if Will tracks down Jack and brings Beckett Jack's magic compass which points to whatever the holder wants most.
Will eventually finds Jack's crew on an island ruled by cannibals, who worship Jack as a god, from which they escape. Shortly after, Governor Swann tries to escape Port Royal with Elizabeth but is captured. Elizabeth negotiates with Beckett to let her escape to find the compass herself, and she hides aboard a Scottish merchant vessel, the Edinburgh Trader. The pirates meet voodoo priestess Tia Dalma (Naomie Harris), who tells them Jones’ weakness is his heart, locked within the Dead Man’s Chest.
Locating the Dutchman, Will, Brian, Peter, Glaceon, and Leafeon get shanghaied into service while Jones sends Jack to bring him one-hundred souls so his blood debt can be paid. On the Dutchman, Will meets his father, and learns that the chest's key is in Jones' possession. On the Dutchman, Brian, Peter, Glacoen, and Leafeon are taken to a big room, and meet Ernie, the Dazzlings, and Dawn Bellwether! Ernie orders them to sit down. Brian refuses, though Glaceon and Leafeon, after getting scared by the Dutchman's crew, convince him they can only obey. Brian knows Ernie is going to use the Ancient Legendary Pokémon: Groudon and Kyogre for his own use. The Dutchman crew growl, making Glaceon and Leafeon afraid, but Brian points out he speaks the truth. Aria Blaze orders them to watch their mouths, while Bellwether replies they want to use the Ancient Pokémon for a better world by unraveling the world's mysteries. She claims that they can also use their powers to defend the world. Brian does not believe her, but Peter knows it would be tough to capture a Legendary Pokémon. But Ernie states they have an Ancient Pokémon already, with the usage of a Red Orb, which shocks them.
Erie tells them Groudon summons volcanoes to expand the land and dispel the thunderstorms that caused floods. Ernie claims they want to use Groudon for the same purpose. Groudon and Kyogre made the world they know today. The Ancient Pokémon they have is Kyogre, which is useless to them, but Ernie also knows that a Blue Orb is trapped in Davy Jones locker. However, the Blue Orb can control Groudon and a Red Orb, can control Kyogre. Since the heroes are a threat to them, Ernie has Adagio to lock them up. After playing a game of liar's dice against Davy Jones, Bootstrap helps Will, Brian, Peter, Glaceon, and Leafeon, escape with the key, but Jones sends the Kraken after him, dragging the destroyed Edinburgh Trader to the depths. And Ernie uses the Red Orb to summon Kyogre to go after them.
In Tortuga, Jack hires a new crew, including Elizabeth, and Norrington, now a drunk. All parties arrive on Isla Cruces where the chest is buried but a three-way sword fight breaks out between Jack, Will, and Norrington who all want the heart for their respective goals: Jack wants to call off the Kraken, Will wants to rescue his father, and Norrington wants to regain his life as a Navy officer. In the chaos, Jack obtains Jones' heart and hides it in a jar of dirt, but Norrington secretly steals the heart and runs off pretending to lure away the Dutchman's crew. Jones attacks the Pearl with the Kraken, which devours most of the crew and destroys all but one of the Pearl's lifeboats, but Jack, who briefly flees the battle, returns and wounds it with a net full of explosives.
Jack orders the survivors to abandon ship, but Elizabeth, realizing that the Kraken only wants Jack, tricks him by kissing him, in the process chaining him to the mast so that the crew can escape the Kraken. Jack manages to break free, but is dragged with the Pearl down to the bottom of the sea by the Kraken. Jones discovers that his heart was successfully stolen and lost. In Port Royal, Norrington approaches Beckett and gives him the heart and Letters of Marque meant for Jack, allowing him back into the navy as well as allowing Beckett to gain control of Davy Jones and the seas. The Pearl’s crew take shelter with Tia Dalma, where they all agree to rescue Jack. Tia Dalma introduces the captain that will guide them: the resurrected Captain Barbossa.
In a post-credits scene, the cannibalistic tribe now worships a dog in replacement of Jack.
- Peter Griffin, Belle, Roger Smith, Bender Bending Rodríguez, Judy Hopps, and Nick Wilde guest star in this film.
- Dawn Bellwether, The Dazzlings, and Ernie the Giant Chicken will work for Davy Jones in this film.
- This film marks it's first appearance of Minerva Mink.
- Beauty and the Beast, Zootopia, and Pirates of the Caribbean: Dead Man's Chest are Disney films.
- The storyline continues in Brian and the Eeveelution Family's Adventures of Pirates of the Caribbean: At World's End.