In order to control the oceans, Lord Cutler Beckett executes anyone associated with piracy in Port Royal by ordering Davy Jones to destroy all pirate ships in the seas. Condemned prisoners sing "Hoist the Colours" to compel the nine Pirate Lords to convene at Shipwreck Cove to hold the Brethren Court. Because Captain Jack Sparrow, Pirate Lord of the Caribbean Sea, never named a successor before being dragged to Davy Jones locker, Captain Barbossa, Will Turner, Elizabeth Swann, Tia Dalma, and the crew of the Black Pearl plot to rescue Jack. Traveling to Singapore, the crew meet Captain Sao Feng (Pirate Lord of the South China Sea), who owns navigational charts to the Locker. Beckett's soldiers invade, but the crew escape. Will secretly promises to give Jack to Feng in return for the Pearl, which he will use to rescue his father Bootstrap Bill Turner from the Flying Dutchman.

The crew travels to the Locker, rescuing Jack and recovering the Black Pearl. The crew encounters many dead souls, including Elizabeth's father Governor Swann, who was executed by Beckett. Tia Dalma reveals that the Goddess Calypso charged Davy Jones with the job to guide the souls of those who died at sea to the next world. Once every ten years he could come ashore to be with the woman he loved. But he corrupted his purpose and was cursed to become a monster. The soul of Governor Swann reveals that whoever kills Jones, by stabbing his disembodied heart, must take his place as the Dutchman's captain.

Returning to the living world, the Pearl stops at an island for fresh water, where the crew find the Kraken lying dead on the beach, having been killed by Jones under orders from Beckett. They are then attacked by Sao Feng and Beckett's men. Through a complex series of deals, Elizabeth is handed over to Feng, who believes she is the goddess Calypso, while the rest of the crew make for Shipwreck Cove aboard the Pearl. Jack throws Will off the ship as part of the plan to seize control of the Dutchman. Sao Feng tells Elizabeth that the first Brethren Court bound Calypso in human form after she betrayed her lover, Davy Jones. He plans to release her to defeat Beckett. Davy Jones attacks Feng's ship, the Empress, mortally wounding Feng in the process. Feng appoints Elizabeth his successor as Pirate Lord before dying. Elizabeth and the crew are locked in the brig of the Dutchman, where she finds Bootstrap Bill losing himself to the Dutchman's curse. In a moment of clarity he tells her that Will must not come, since by killing Jones he will bind himself to the ship. Admiral Norrington frees Elizabeth and her new crew from the Dutchman, but is killed by Bootstrap Bill.

The Black Pearl arrives at Shipwreck Cove, where Barbossa attempts to persuade the Brethren Court to release Calypso. Davy Jones visits Tia Dalma in the Pearl's brig, revealing she is Calypso. Jack's father Captain Teague, Keeper of the Pirate Code, informs the Court that only an elected Pirate King can decide on going into battle. A vote is taken. To avoid a stalemate, Jack casts his vote for Elizabeth, making her King.

The Brethren Court and Beckett's fleets emerge for war. On a sandbank, Elizabeth, Jack, Barbossa, Beckett, Jones, and Will parley, trading Will for Jack. Barbossa steals Jack's piece of eight, all of which are owned by the Pirate Lords and required to free Calypso. Barbossa frees Calypso, but when Will reveals it was Jones who betrayed her and made it possible for the first Court to imprison her, Calypso vanishes and summons an enormous maelstrom.

The Pearl and the Dutchman battle in the maelstrom. Elizabeth and Will are wed by Barbossa. On board the Dutchman, Jones and Jack engage in a duel for control of Davy Jones' heart. Jones stabs Will, mortally wounding him. Jack gives up his chance for immortality and instead helps Will stab the heart, killing Jones, whose body falls into the maelstrom. Jack and Elizabeth escape the Dutchman as it is sucked into the maelstrom.

As Beckett's ship, the Endeavour, approaches to destroy the Pearl, the Dutchman rises from the sea, now captained by Will; the crew has been freed from Jones' curse. Together, the two pirate ships destroy the Endeavour. A stunned Beckett goes down with his ship while his navy retreats. With Will now forever bound to escort souls lost at sea to the next world, he and Elizabeth bid farewell to each other on the beach of an abandoned island. Will departs on the Dutchman, leaving Elizabeth pregnant and with the chest containing his heart.

Jack and Joshamee Gibbs discover Barbossa has stolen the Black Pearl again, but Jack planned ahead and stole Sao Feng's navigational charts. He departs from Tortuga alone to track down the mythical Fountain of Youth.

In a post-credits scene, set ten years later, Elizabeth and her son Henry watch from a sea cliff as Will returns aboard the Dutchman.

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