The System of the World begins where the first book of the Baroque Cycle trilogy, Quicksilver, concluded. Daniel Waterhouse, chancellor of the Massachusetts Colony Institute of Technical Studies and Arts, is returning to London from Boston aboard the ship Minerva. He has not been back long when an attempt is made on his life. The would-be assassins unsuccessfully use an infernal device, or time bomb and an exhaustive search for the culprit begins. As Daniel comes to grips with this, England in 1714 continues to search for an heir to the throne for Queen Anne, who is terminally ill. The Queen populates the House of Lords with Tories and a struggle for power continues in the background throughout the story's plot.

Daniel tries to reconcile differences between Sir Isaac Newton and Gottfried von Leibniz in their ongoing dispute over the invention of calculus. Meanwhile, the English Mint, which Sir Isaac is the master of and accountable for, is under question because of allegations that the English currency is not authentic. The trial of the Pyx will test its merit.

Jack Shaftoe, Sir Isaac's nemesis and an expert counterfeiter, has stolen and tampered with the contents of the Pyx, the English Mint's sampling box. This not only subjects the English economy to failure but also brings Sir Isaac's integrity into question. Jack is an elusive character who constantly toys with Sir Isaac, often making the extremely intelligent man appear foolish. This emerges as a satirical element woven through the plot, illustrating the author's interpretation that while Sir Isaac may have been a mathematical genius, he was not brilliant in all areas.

Jack eventually confesses to his counterfeiting crimes and is sentenced to death. However, he has earned a reputation amongst the common English folk and his popularity saves his life. Jack's rescue leaves the authorities believing he has perished. Unable to supply a body as evidence, the authorities assume the commoners have stolen Jack's remains for sacred burial and they think nothing more of it. This is far from the truth and Jack is reunited with his long-lost love Eliza, the Duchess of Qwghlm.

Leibniz returns to Germany without resolving the dispute with Sir Isaac and he resigns himself to dying without reconciliation. Sir Isaac's reputation is upheld when his name is cleared. The English currency's quality is proven at the trial of the Pyx, the English economy remains intact and Daniel's inventions continue to astound. The system of the world has evolved and strengthened, its fate decided and the Industrial Age is coming about.

The System of the World is a tale of deception, political propaganda, ill-gotten gains and a struggle for recognition and power. It contrasts historical data with that of fictitious science fiction, making it a believable yet quirky tale.