After a failed attempt to rescue his first mate, Joshamee Gibbs, in London, Captain Jack Sparrow is brought before King George II, who wants Jack to guide an expedition to the Fountain of Youth before his Spanish rivals can locate it. Heading the expedition is Jack's old nemesis, Captain Hector Barbossa, now a privateer in service to the Royal Navy after losing his leg and ship, the Black Pearl.
Jack escapes, but his father, Captain Teague, finds him and warns Jack about the Fountain's rituals. He also discloses that someone is impersonating Jack. The impostor is Angelica, Jack's former lover and the daughter of the ruthless pirate Blackbeard, who practices voodoo magic and wields a magical sword that controls his ship, the Queen Anne's Revenge.
Jack is taken aboard the Queen Anne's Revenge, and forced to lead the way to the Fountain and find two silver chalices that once belonged to Juan Ponce de León, both believed to be aboard his missing flagship. The Fountain's water must be consumed simultaneously from the two special chalices. Any individual drinking from the chalice containing a mermaid's tear has their life extended, while the other dies, their life drained from their body and remaining years 'donated' to the other. Meanwhile, Gibbs narrowly escapes execution by memorizing and destroying Jack's personal map, forcing Barbossa to spare him so he could navigate to the Fountain.
Blackbeard seeks the Fountain's power to circumvent his predestined fatal encounter with "a one-legged man," (Barbossa) and charts a course for Whitecap Bay - where he hopes to harvest tears from a mermaid. A small boat of mutineers are set adrift as bait; led by Tamara, the mermaids obligingly seduce and massacre them. In the ensuing battle Blackbeard captures one. Philip Swift, a captive missionary, falls in love with the mermaid and names her Syrena. Reaching the uninhabited island where de León's last voyage ran aground, Angelica and Blackbeard coerce Jack into retrieving both Fountain chalices. By the time he finds the explorer's decaying vessel, however, Barbossa and a Spanish expedition have reached it first.
Barbossa declares he is only interested in seeking revenge against Blackbeard for attacking the Black Pearl, which forced him to amputate his own leg to escape. He and Jack join forces to defeat Blackbeard, then head to the nearby Spanish camp to steal the chalices. Meanwhile, Syrena, reciprocating Philip's love, is tricked into shedding a tear which Blackbeard collects, leaving her to die. Philip is forced to continue as a hostage. Jack returns with the chalices and Gibbs, with whom he had reunited while assisting Barbossa. Jack and Blackbeard bargain for Jack's confiscated magical compass and Gibbs' release. In return, Jack vows to give Blackbeard the chalices and lead him to the Fountain; Blackbeard agrees and Gibbs departs with the compass.
At the Fountain, Blackbeard's crew are confronted by Barbossa and subsequently by Spanish authorities there to demolish the site, which they maintain is an abomination against God. A vicious skirmish breaks out and Barbossa stabs Blackbeard with his poisoned cutlass. Angelica pulls the sword out of Blackbeard but is cut and poisoned, too. Philip is also mortally wounded in the melee. Nevertheless, he returns to liberate Syrena, who retrieves the missing chalices and gives them to Jack, telling him not to waste her tear. Syrena finds Philip, who is dying. Philip asks Syrena for her forgiveness. She kisses him and they disappear underwater together.
With Blackbeard and Angelica nearing death, Jack brings the chalices to them and tries to convince Angelica to drink from the one with the tear, but Blackbeard asks his daughter to sacrifice herself. Angelica agrees. Knowing that the self-serving Blackbeard would sacrifice his daughter, Jack lies about which chalice contains the tear. Angelica's wounds are healed while the Fountain consumes Blackbeard's body, killing him. Although Angelica confesses her love for Jack, he remains uneasy about her intentions and leaves her stranded on a cay barefoot with a pistol containing one shot. Angelica fires the shot at Jack as he rows away, but misses. Barbossa absconds with the Queen Anne's Revenge, having returned to piracy.
Jack finds Gibbs, who has used his compass to locate the shrunken Black Pearl in a bottled collection of ships imprisoned by Blackbeard. Hoping to find a way to revert the Black Pearl to its original size, the two head off into the sunset, determined to continue their pirate life.
In a post-credits scene, a voodoo doll of Jack crafted by Blackbeard washes ashore and is claimed by a grinning Angelica.
- 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, Foop, 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: Dead Men Tell No Tales.
- 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
- Penélope Cruz as Angelica
- Geoffrey Rush as Captain Hector Barbossa
- Ian McShane as Captain Blackbeard
- Kevin McNally as Joshamee Gibbs
- Sam Claflin as Philip Swift
- Àstrid Bergès-Frisbey as Syrena
- Stephen Graham as Scrum
- Greg Ellis as Lt. Cmdr. Theodore Groves
- Damian O'Hare as Lt. Gillette
- Óscar Jaenada as The Spaniard
- Richard Griffiths as King George II
- Keith Richards as Captain Edward Teague
- Gemma Ward as Tamara
- Judi Dench as Society Lady
- Ian Mercer as the Quartermaster
- Robbie Kay as the Cabin Boy
- Christopher Fairbank as Ezekiel
- Yuki Matsuzaki as Ghareg
- Bronson Webb as The Cook
- Steve Evets as Purser
- Derek Mears as the Master-at-Arms
- DeObia Oparei as the Gunner
- Sebastian Armesto as King Ferdinand of the Spanish Empire
- Anton Lesser as Lord John Carteret, Viscount Carteret, Baron Carteret of Hawnes, 2nd Earl of Granville
- Roger Allam as Prime Minister Henry Pelham
- Paul Bazely as Salaman
- 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