In mid-18th century, a man is rescued from the ocean off the Spanish coast and brought to King Ferdinand of Spain, where he claims to be a crewmate of Juan Ponce de León, who disappeared 200 years ago searching for the Fountain of Youth. Seventeen years after the battle of Calypso's maelstrom,^{[N 1]} after a failed attempt to rescue his first mate, Joshamee Gibbs, from execution in London, Captain Jack Sparrow is brought before King George II. The king asks Jack to guide an expedition to locate the Fountain of Youth, before King Ferdinand and the Spanish Navy locate it. Captain Hector Barbossa, now a privateer, and sporting a peg leg, is captaining the expedition, though only requires Sao Feng’s navigational charts, rather than Jack's.

Jack escapes, meeting his father, Captain Teague, who tells Jack that the Fountain requires a ritual to use. Jack learns an impersonator is recruiting pirates for another expedition. The imposter is Angelica, Jack's former lover, and daughter of the legendary Blackbeard. Jack is shanghaied into service on board Blackbeard's ship, the Queen Anne's Revenge. Blackbeard survived his historic death using voodoo magic, due to a predestined, fatal encounter with Barbossa. He wields the Sword of Triton, which allows him to control his ship. Though Jack leads a mutiny, Blackbeard subdues the crew into obedience. Amongst the crew is Philip Swift, a captured missionary.

Barbossa recruits Gibbs, who burns the charts, admitting he memorized every location. Jack is told by Angelica that two silver chalices must be retrieved from Ponce de León's flagship, the Santiago. A mermaid’s tear must be placed in one chalice, and both chalices must be drunk simultaneously to activate the Fountain's healing properties. The drinker who lacks the tear will die, their lifeforce is given to the other. Jack discovers Blackbeard's collection of captured, miniaturized ships, including the Black Pearl.

The Revenge sails to Whitecap Bay to capture a mermaid, successfully netting Syrena, who they, at first, must carry in a glass container. When Syrena is dropped, her tail turns into legs. Philip, caring for her, (and seeing she cannot walk) offers to carry her. After reaching Whitecap Bay, Barbossa, Gibbs, and a few British sailors are forced to continue in rowboats after their ship and its crew is attacked by the mermaids.

Angelica and Blackbeard send Jack to get the chalices, taking his magic compass as a bargaining chip. Jack meets Barbossa on the Santiago but finds the chalices have been taken by the Spanish. Retrieving the chalices, Barbossa explains Blackbeard attacked the Black Pearl, leading to the loss of his leg via self-amputation. Syrena's tear is extracted by Blackbeard after Philip expresses love for her, leaving her to die of dehydration, and Philip is forced to go with the crew.

Jack returns, bargaining for the return of his compass in exchange for the chalices. When Blackbeard agrees, Jack sends Gibbs off on an errand. Blackbeard's crew locates the Fountain but is confronted by Barbossa and his men. The Spanish arrive, condemning the Fountain as an abomination against God, throwing the chalices into a deep pool. In the chaos, Philip frees Syrena, who retrieves the chalices, returning them to Jack. Barbossa stabs Blackbeard with his poisoned sword, steals the Sword of Triton, declares himself captain of the Revenge, and returns to a life of piracy.