Set in New York's notoriously corrupt Tammany Hall era following the Civil War, The Printer's Devil follows Ambrose Kelly, a type-setter for The Tribune. Ambrose has come far in life since his impoverished youth, when he supported his mother and siblings as a bare knuckles fighter. In 1870, Ambrose's dreams are shattered when his wife Maeve and son Edward are run down by a beer wagon. Suspecting murder, Ambrose is intent on tracking down the killers. He arranges for his disabled niece Addie to move in and care for his three year old daughter Nola. Ambrose believes his wife and son were killed because of his side trade in acquiring old books for wealthy patrons. But there may be a different cause - strong-arm work he did for Tammany Hall as a young man. Boss Tweed faces investigation and Ambrose knows that Tammany wouldn't hesitate to silence potential witnesses. Ambrose receives unexpected help from Maisie Rourke, his little sisters' childhood friend. The 19th century equivalent of a call girl, Maisie knows everyone from Samuel Clemens to Jay Gould to George Vandermeer, the shipping magnate who originally commissioned the search for St. Mathew's gospel. After three attempts on Ambrose's life, his former boss Horace Greeley sends him to the Ottoman Empire as a correspondent, enabling Ambrose to track Vandermeer. After discovering Maisie's skill at art, Greeley hires her as Ambrose's illustrator. Together, they follow Vandermeer from Constantinople to a Georgian monastery to the Caspian to Cairo and Luxor and Abyssinia in a deadly race to find the gospel first. Meanwhile, Nola is kidnapped and Addie, though deaf and mute, must search New York alone. While Ambrose wards off his enemies and protects his family, he also must settle his confused feelings between grief for Maeve and Edward, a budding romance with Maisie, and attraction to his niece (by marriage) Addie, who reminds him so much of Maeve.