The year is 1796, and a trading ship arrives in the vibrant trading town of Newburyport, Massachusetts. But it's a ghost ship--her entire crew has been decimated by a virulent fever which sweeps through the harbor town, and Newburyport's residents start to fall ill and die with alarming haste. Something has to be done to stop the virus from spreading further. When physician Giles Wiggins places the port under quarantine, he earns the ire of his shipbuilder half-brother, the wealthy and powerful Enoch Sumner, and their eccentric mother, Miranda. Defiantly, Giles sets up a pest-house, where the afflicted might be cared for and separated from the rest of the populace in an attempt to contain the epidemic.

As the seaport descends into panic, religious fervor, and mob rule, bizarre occurrences ensue: the harbormaster's family falls victim to the fever, except for his son, Leander Hatch, who is taken in at the Sumner mansion and a young woman, Marie Montpelier, is fished out of the Merrimac River barely clinging to life, causing Giles and Enoch-who is convinced she's the expatriate daughter of the French king-to vie for her attentions--all while medical supplies are pillaged by a black marketer from Boston. As the epidemic grows, fear, greed, and unhinged obsession threaten the Sumner family-and the future of Newburyport itself.