It's 1729 and the HMS Petrel, a British vessel, travels the open seas with a valuable item in tow - the longitude chronometer, a world-changing invention that allows for accurate time-keeping and navigation during long voyages, a capability that threatens to end piracy. That is, unless pirates manage to get it first - which appears inevitable when a ship full of pirates intercepts the Petrel and commences a bloody battle onboard, led by fearless warriors Nenna Ajanlekoko and Charlie Rider.
Meanwhile, British ship's physician Tom Lowe recognizes what the pirates want, swiftly locates the chronometer - and destroys it! As its inventor, Benedict Nightingale, reacts in abject horror, Lowe takes an extra step and shoves poison down the man's throat - right as Nenna and Rider arrive, fresh off their victory. The two pirates capture Lowe, along with his young assistant, Fletch, and demand that he keep Nightingale alive. With the Petrel under new control, sails redirect to the heretofore-unknown island of Santa Campana, home to a rogue nation of thieves and ruled by a ruthless man most of the world thinks is dead... Blackbeard.
Known on the island as either Commodore or his given name, Edward Teach, Blackbeard's introduction to Lowe leaves little mystery: he demands Lowe keep Nightingale alive or suffer a tortuous death. As Lowe tends to the inventor, Nenna and Rider present Blackbeard's second in command, Selima El Sharad, with a cipher for the chronometer's blueprints; without the key, however, she doubts her ability to break it. So when Nightingale's state worsens and he dies in Lowe's care, rebuilding the chronometer seems unlikely - and Lowe's death imminent - until the physician reveals he memorized the cipher's key. Blackbeard grants him a temporary stay of execution.
As Lowe works tirelessly to decode the cipher, Fletch begs for them to flee. His insistence forces Lowe to admit an ulterior motive for breaking the cipher and endearing himself to Blackbeard. Although Lowe is indeed a trained physician, his true loyalty lies with the British crown and the governor of Jamaica, who employed him for one task: assassinate Blackbeard.
At that very moment, Selima bursts in and tortures Lowe for the key code. A desperate Fletch runs to Blackbeard and interrupts a brothel visit to alert the Commodore - a move that saves his friend, Lowe, but results in a harsh beating from Rider. Blackbeard promises to keep Lowe safe, but blackmails him with a threat to harm every fiber of Fletch's being if he dawdles in his quest to decrypt the cipher.
This spurs Lowe to fast-track his assassination plan in order to save both his skin and Fletch's. He sneaks out of their room to retrieve an important locket from among the Petrel's loot inventoried in the quartermaster's home - and soon finds himself on the wrong end of the quartermaster's sword. When beautiful British fugitive Kate Balfour grills him on the purpose of his visit, Lowe lies about the locket, claiming it contains the only image of his deceased wife. She shows mercy - or is it an attraction? - and allows him to leave with the locket... which actually hides a tiny vial of poison.
That night, Lowe meets Blackbeard and finds him suffering from excruciating headaches. With some reluctance Blackbeard admits that he often sees visions, too. Lowe clocks this information before gifting Blackbeard the cipher key and Nightingale's accompanying journal. He offers all this in exchange for Blackbeard's word that he will not hurt Fletch. Blackbeard agrees, and later, as Lowe and Fletch make their escape from Santa Campana, Blackbeard falls ill, unable to breath, all due to the invisible poison at the edges of the journal's pages.
But as Lowe and Fletch rush to their getaway boat, they spot pirates guiding a blindfolded Spaniard on the coast, clearly in secret. Lowe recognizes him as the viceroy of Spain, sworn enemy of England. Is Blackbeard conspiring with Spain? Lowe realizes that if Blackbeard dies, he may never figure out the connection and thus risk the lives of his countrymen. He must save Blackbeard.
Lowe marches back to mansion with the antidote, greeted by a dying Blackbeard writhing on the floor and a vengeful Selima armed with two guns. He pleads with her to allow him to cure Blackbeard - lying again that Blackbeard suffers from "the falling sickness" - but she refuses to listen and shoots him in the shoulder! Wounded, Lowe presses on and smacks away her weapons, fighting to stay conscious while he administers the cure. Once he hears Blackbeard's breathing commence, Lowe collapses.
Later, a recovered Blackbeard visits James Balfour, Kate's wheelchair-bound husband, and inquires about the prospect of building a chronometer from the decrypted blueprints. Balfour speaks of its possibility... but mostly they chat about Lowe. Can he be trusted? Blackbeard answers bluntly - he hasn't decided yet.