Captain Jack Sparrow finds himself on an unexpected journey to the fabled Fountain of Youth when a woman from his past, Angelica, forces him aboard the Queen Anne's Revenge, the ship captained by the fearsome pirate Blackbeard. Angelica, posing as Jack at first, is revealed to be Blackbeard's daughter, and she is driven by the prophecy that her father will meet a grim fate if he does not find the Fountain. Blackbeard, a practitioner of dark magic, seeks the Fountain's power for immortality. Jack, caught between the mistrust of Angelica and the tyranny of Blackbeard, must use all his wiles to navigate the treacherous waters ahead.

Meanwhile, the British Royal Navy has also set sights on the Fountain, led by Captain Barbossa, now a privateer in service to King George II and a vengeful rival of Jack, having lost a leg and his ship, the Black Pearl, to Blackbeard. Barbossa seeks the Fountain not only for the glory of the crown but to settle his personal score. As both parties race against time and each other, they must confront mermaids, hostile natives, and each other's deceptions. Unbeknownst to them, the Spanish crown also has an interest in the Fountain, but for reasons of their own, sending all the parties towards a confrontation where motives, allegiances, and destinies will clash.