To control the oceans, Lord Cutler Beckett kills anyone associated with piracy and uses Davy Jones to destroy all pirate ships on the seas. Condemned prisoners sing "Hoist the Colours" to compel the nine pirate lords to convene at Shipwreck Cove; however, the late Captain Jack Sparrow, pirate lord of the Caribbean, never appointed a successor. Captain Barbossa leads Will, Elizabeth,Tia Dalma and the crew of the Black Pearl to rescue Jack from Davy Jones's Locker. Sao Feng, pirate lord of the South China Sea, possesses a map to the Locker called "The Navigation Charts". Will bargains with Feng for the Pearl in exchange for Sparrow, so Will can rescue his father from Davy Jones' ship, The Flying Dutchman. The crew journeys into the Locker and retrieves Sparrow. As the Pearl seeks an escape route, dead souls float past, including Elizabeth's father Weatherby Swann. Tia Dalma reveals that Davy Jones was appointed by Calypso, his lover and goddess of the Sea, to ferry the dead to the next world; in return, Jones could step upon land for one day every ten years. When she failed to meet him, he abandoned his duty and transformed into a monster.
After returning to the living world, the Pearl is ambushed by Sao Feng. Feng betrays Will, handing over the crew to Beckett in exchange for the Pearl. Beckett takes Sparrow aboard his vessel, the Endeavour. Feng bargains with Barbossa to release the Pearlin exchange for Elizabeth, who he believes is Calypso. Feng's ship attacks the Endeavour, allowing Jack to escape. Feng tells Elizabeth that the first Brethren Court trapped Calypso in human form so men could rule the seas. When Davy Jones attacks Feng's ship, the mortally wounded Feng appoints Elizabeth as his successor, and she and the crew are imprisoned in the Flying Dutchman 's brig. Bootstrap Bill Turner reveals to Elizabeth that the person who stabs Davy Jones' heart becomes the next captain of the Dutchman. Admiral Norrington is killed while freeing Elizabeth and her crew.
Jack catches Will, and they discuss Davy Jones' heart. Jack suggests he stab the heart to solve Will's conflicting obligations, then tosses Will overboard after giving him his compass so Beckett can find Shipwreck Cove. Meanwhile on the Pearl, Davy Jones appears to Calypso, now revealed to be Tia Dalma, and asks why she left him. Calypso reveals that she will only let the Brethren Court free her so she can show them just how cruel she can be.
Back at Shipwreck Cove, Barbossa calls upon Captain Teague, Jack's father and Keeper of the Pirate's Code, to confirm that only a Pirate King can declare war. Jack calls for a vote, the first eight Lords vote for themselves, and Jack breaks the stalemate by voting for Elizabeth, who favors war, wanting revenge on Beckett for her father's death. During aparley with Beckett and Jones, Elizabeth swaps Sparrow for Will after realizing Jack and Will plan to have Jack stab the heart.
Barbossa steals Jack's "piece of eight" and uses it and its counterparts to free Calypso. Will discloses that Davy Jones betrayed her to the Brethren Court, and Calypso's fury unleashes a maelstrom, in which the Dutchman and the Pearl battle. Sparrow escapes the Dutchman 's brig and steals the Dead Man's Chest, which leads to a sword battle with Jones. Will proposes to Elizabeth in the middle of a swordfight, who accepts his proposal, and Captain Barbossa marries them. Will boards the Dutchman to retrieve the chest, but is mortally wounded by Jones. Sparrow places his sword in Will's hand and helps Will stab Jones's heart before Will dies. Sparrow and Elizabeth escape the Dutchman as it sinks in the maelstrom. Beckett moves to attack the Pearl but the Dutchman resurfaces with Will as the captain and the crew returned to their human forms. The Dutchman and the Pearl destroy the Endeavour, killing Beckett. The East India Trading Company armada, leaderless, retreats.
Will is bound to sail the sea as the Dutchman 's captain. Elizabeth bids Jack, Barbossa and the crew farewell before Will and Elizabeth have one day together. He departs after giving Elizabeth the Dead Man's Chest. Barbossa commandeers the Pearl, stranding Jack and Gibbs in Tortuga, in order to find the Fountain of Youth, only to discover Jack cut out the middle of the map. Jack sails from Tortuga in a small boat to find the Fountain of Youth.
In a post-credits scene set ten years later, Elizabeth and her son watch from a seacliff, as the Dutchman appears with Will Turner aboard, prompting Will's "one day on land" to spend with Elizabeth.
- The Human Mane 5, The DigiDestined and their Digimon (Digimon Frontier), Timmy Turner, Cosmo and Wanda, Chloe Carmichael, Tara Duncan, Cal (Tara Duncan), Sparrow, Ranamon, Lucemon, Hunter J, Attila and Hun, Norm the Genie, and Kurumi Tokisaki will guest stars in this film.
- Sunset Shimmer will be absent in this film. So Sonic876 replaces her with Juniper Montage.
- The storyline continues in Weekenders Adventures of Pirates of the Caribbean: On Stranger Tides.
- Jason Marsden as Tino Tonitini
- Grey DeLisle as Lor McQuarrie
- Phil LaMarr as Carver Descartes
- Kath Soucie as Tish Katsufrakis
- Tara Strong as Sci-Twi
- Cathy Weseluck as Spike the Dog
- Ali Liebert as Juniper Montage
- Josh Grelle as Shido
- Michelle Rojas as Tohka
- Bryn Apprill as Kotori
- Tia Ballard as Yoshino
- Michelle Lee as Origami
- Felecia Angelle as Mana
- Carly McKillip as Sakura Kinomoto
- Ashleigh Ball as Rainbow Dash/Applejack
- Andrea Libman as Pinkie Pie/Fluttershy
- Tabitha St. Germain as Rarity
- Tara Strong as Timmy/Poof
- Daran Norris as Cosmo
- Susanne Blakeslee as Wanda
- Kari Wahlgren as Chloe Carmichael
- Michael Reisz as Takuya Kanbara
- Michelle Ruff as Zoe Orimoto
- Steven Blum as Junpei "J.P." Shibayama
- Brianne Siddall as Tommy Himi
- Steve Staley as Koji Minamoto
- Crispin Freeman as Koichi Kimura
- Brian Beacock as Bokomon
- Michael Sorich as Neemon
- Saffron Henderson as Tara Duncan
- Kelly Metzger as Sparrow
- Matt Hill as Cal
- Johnny Depp as Captain Jack Sparrow
- Geoffrey Rush as Captain Hector Barbossa
- Orlando Bloom as William "Will" Turner Jr.
- Keira Knightley as Captain Elizabeth Swann
- Jack Davenport as James Norrington
- Bill Nighy as Captain Davy Jones
- Jonathan Pryce as Weatherby Swann
- Lee Arenberg and Mackenzie Crook as Pintel and Ragetti
- Kevin McNally as Joshamee Gibbs
- David Bailie as Cotton
- Stellan Skarsgård as William "Bootstrap Bill" Turner, Sr.
- Chow Yun-fat as Captain Sao Feng
- Tom Hollander as Cutler Beckett
- Naomie Harris as Tia Dalma / Calypso
- Martin Klebba as Marty
- David Schofield as Mr. Mercer
- Keith Richards as Captain Edward Teague
- Greg Ellis as Lieutenant Theodore Groves
- Lauren Maher and Vanessa Branch as Scarlett and Giselle
- Angus Barnett and Giles New as Mullroy and Murtogg
- Reggie Lee as Tai Huang
- Peggy O'Neal as Ranamon
- Mona Marshall as Lucemon
- Alexis Tipton as Kurumi
- Norm MacDonald as Norm the Genie
- Shannon Conley as Pokémon Hunter J
- Marc Thompson as Attila
- Veronica Taylor as Hun