The wedding of Will Turner and Elizabeth Swann is interrupted by Lord Cutler Beckett of the East India Trading Company, who hasarrest warrants for them after they aided Captain Jack Sparrow escaping execution a year ago, and one for Commodore James Norrington, for delaying the pursuit of Sparrow, but he resigned from his position and disappeared months prior. Elizabeth is imprisoned. Beckett sends Will to find Jack's magic compass, which points to whatever the holder wants the most at the time, in exchange for Letters of Marque which will make Jack a British privateer and ensure Will and Elizabeth's pardon. Shortly after Will leaves, Governor Swann, Elizabeth's father, tries to flee Port Royal with her, but he is arrested by Beckett's aide Mercer. Beckett allows Elizabeth to go after Will, giving her the Letters of Marque.
Jack escapes a Turkish prison after acquiring a drawing of a key he desires, but his compass fails to provide him a heading. On theBlack Pearl, Jack reunites with Will's father Bootstrap Bill, who joined the crew of Davy Jones to escape his death. Bootstrap reminds Jack of the deal he made with Jones thirteen years ago to raise the Black Pearl from the depths, and now he must either join his crew or be dragged to Jones’ Locker by his pet, the Kraken. Panicked, Jack takes the ship to land, ending up on Pelegosto. Will arrives on the island and is taken captive by cannibals, but he and surviving crew members escape to the Black Pearl with Jack, joined by Pintel and Ragetti. The crew visit voodoo priestess Tia Dalma, who reveals the key of the Dead Man's Chest, in which Jones put his own heart after being betrayed by his lover. Tia Dalma tells Jack where to find Jones’ ship — the Flying Dutchman — and gives him a jar of dirt as a defense against the Kraken.
Jack forces Will onto a shipwreck, only for the actual Flying Dutchman to emerge from the ocean and take Will prisoner. Jones confronts Jack, who makes a deal to break his debt if he brings Jones one hundred souls in three days but Will has to stay on the Dutchman. Bootstrap helps him escape the ship, with the key from Jones. Will promises to use the heart to free Bootstrap. Jack goes to Tortuga to recruit new crewmates, meeting Elizabeth and Norrington, who has become a drunkard. Both of them join the Black Pearl. Jack realises that if Beckett gains Jones’ heart, he will rule the seas. Norrington eavesdrops, planning to get the heart in order to regain his life and honour. Will hitches a ride on the Edinburgh Trader, which is destroyed by the Kraken, and Jones realises that Jack is after the chest.
All parties arrive on Isla Cruces, but a three-way sword fight breaks out between Jack, Will and Norrington to pursue their own goals, while Jones’ crew attack Elizabeth, Pintel and Ragetti. In the chaos, Jack unlocks the chest, removes the heart, and hides it in the jar of dirt, only for Norrington to steal it and pretend to sacrifice himself by drawing theDutchman crew off with the chest. Jack, Will, Elizabeth and the Black Pearl crew are confronted by the Flying Dutchman but the Black Pearl outruns it. Jones summons the Kraken, which traps the Black Pearl. Jack discovers that the heart is missing and abandons his crew, but returns when he sees the Kraken destroying the ship, wounding the Kraken with a net full of explosives. Jack orders the survivors to abandon the ship, but he is chained to the mast by Elizabeth. After they leave, Jack manages to free himself from the chain, but is dragged into Davy Jones' Locker.
Jones fails to find his heart. Norrington reaches Port Royal, presenting the heart to Beckett. Will, Elizabeth, Gibbs, Pintel, Ragetti, Marty and Cotton return to Tia Dalma's house, where she asks if they wish to rescue Jack from the locker, to which they agree. Tia Dalma says they will need a captain who is familiar with the waters. The captain appears, and to their surprise, it is Captain Barbossa.
- 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: At World's End.
- 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
- Saffron Henderson as Tara Duncan
- Kelly Metzger as Sparrow
- Matt Hill as Cal
- Johnny Depp as Captain Jack Sparrow
- Orlando Bloom as William "Will" Turner, Jr.
- Keira Knightley as Elizabeth Swann
- Bill Nighy as Captain Davy Jones
- Jack Davenport as James Norrington
- Stellan Skarsgård as William "Bootstrap Bill" Turner, Sr.
- Kevin McNally as Joshamee Gibbs
- Jonathan Pryce as Governor Weatherby Swann
- Lee Arenberg as Pintel
- Mackenzie Crook as Ragetti
- Tom Hollander as Lord Cutler Beckett
- Naomie Harris as Tia Dalma
- David Bailie as Cotton
- Martin Klebba as Marty
- David Schofield as Ian Mercer
- Alex Norton as Captain Bellamy
- Geoffrey Rush as Captain Hector Barbossa
- Dermot Keaney as Maccus
- Andy Beckwith as Clanker
- Clive Ashborn as Koleniko
- Reggie Lee as Hadras
- Christopher Adamson as Jimmy Legs
- Jonathan Linsley as Ogilvey
- John Boswall as Wyvern
- Max Baker as Burser
- Steve Speirs as Quartermaster
- 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