After a failed attempt to rescue his former first mate, Joshamee Gibbs (Kevin McNally) in London, England, Jack is brought before King George II (Richard Griffiths). The king wants Jack to guide an expedition to the Fountain of Youth before the Spanish locate it. Heading the expedition is Jack's old nemesis, Captain Hector Barbossa (Geoffrey Rush), now a privateer in service to the British Navy after having lost Jack's ship, the Black Pearl, as well as his leg.
Jack escapes, but his father, Captain Teague (Keith Richards), finds him and warns Jack about the Fountain's tests. He also reveals that someone is impersonating Jack. The impostor is Angelica (Penélope Cruz), Jack's former lover and daughter of the ruthless pirate Blackbeard (Ian McShane), who possesses supernatural powers and practices voodoo magic.
Jack is taken aboard Blackbeard's ship, the Queen Anne's Revenge, and forced to lead the way to the Fountain, and to find two silver chalices once belonging to Juan Ponce de León, believed to be aboard his grounded ship. The Fountain's water must be drunk simultaneously from the two chalices. The person drinking from the chalice containing a mermaid's tear has their life extended, while the other person dies, their years of life drained from their body. Meanwhile, Gibbs barters with Barbossa to guide him and his crew to the Fountain, as he has memorized and destroyed Sparrow's map.
Blackbeard wants the Fountain's power to circumvent his predestined fatal encounter with a one-legged man, and sets a course for Whitecap Bay. There, he traps a mermaid (Àstrid Bergès-Frisbey) that Philip Swift (Sam Claflin), a captive missionary, falls in love with and names Syrena. Blackbeard then sends Sparrow to retrieve the chalices from de León's ship. When Sparrow finds the decaying vessel, Barbossa is waiting inside: the Spanish have already taken the chalices.
Barbossa, who only seeks revenge against Blackbeard for capturing the Black Pearl and forcing Barbossa to amputate his own leg to escape, joins forces with Jack to defeat Blackbeard. They then head to the nearby Spanish camp to steal the chalices. Meanwhile, Syrena, who returns Philip's love, is tricked into shedding a tear, which Blackbeard collects, then leaves her to die while forcing Philip to go with him. Sparrow returns with the chalices and Gibbs, who he had reunited with while helping Barbossa. Jack negotiates with Blackbeard to return his confiscated magical compass and to let Gibbs go free in exchange for the chalices and his leading them to the Fountain. Blackbeard agrees, and Gibbs departs with Jack's compass.
At the Fountain, Blackbeard and his crew are attacked by Barbossa, then the Spanish, sent by their king to destroy the Fountain, believing its power is an abomination against God. After an intense battle, Barbossa stabs Blackbeard with a poison-laced sword that also wounds Angelica. Barbossa claims Blackbeard's magical sword, and assuming command, leaves with Blackbeard's crew. Philip, though mortally wounded, escapes and returns to free Syrena. After finding the chalices that the Spaniards had tossed into deep water, Syrena gives them to Jack, then retrieves the dying Phillip, taking him underwater to save his life.
As both Blackbeard and Angelica lay dying, Blackbeard wants his daughter to sacrifice herself to save him. Angelica willingly agrees, but Jack secretly switches the chalices, giving her the one containing the tear, thus sparing her life and killing Blackbeard. Although they declare their love, Jack, knowing she may avenge her father's death, strands her on an island (with only a pistol loaded with one shot), intending for a passing ship to pick her up. Meanwhile, Barbossa, who now commands the Queen Anne's Revnege, renounces his ties to the crown and reverts to piracy. Jack finds Gibbs, who used Jack's compass to locate the Revenge and retrieve the Black Pearl, as well as the other captured ships that Blackbeard had magically shrunk and bottled. The two head off, hoping to find a way to return the Pearl to its original size.
In a post-credits scene, Angelica, still on the island, finds Blackbeard's voodoo doll of Jack, which has washed ashore.