Chapter 3 describes the breadth and size of the Inca Empire and its zenith, before narrating the circumstances of its fall to the Spanish conquistador, Francisco Pizarro, and his forces. The author emphasizes the size of the Inca Empire compared to its contemporaries—Imperial Russia, the Sahel, the Ming Dynasty—and the variety of climates and terrain, from rainforest jungles to desert plains and mountain terraces. A significant portion of the chapter is given to the prior rulers of the Inca Empire, including Pachakuti Inca, and TopaInca Yupanki. It is their military gains and publics that make the Empire as massive—and vulnerable—as it is when the conquistadors arrive. Eventually, a civil war between half-brothers Huaskar and Atawallpa, each vying to be ruler, would embroil the entire Empire.

Pizarro invades the Inca Empire in the midst of this civil war, ransoming and executing Atawallpa, who had not long before ordered the execution of Huaskar. Although this was only the beginning of the Spanish conquest of the Inca Empire, the power vacuum in an over-centralized Inca Empire would prove beneficial for the Spaniards. However, in addition to this, Mann posits that the fall of the Inca Empire was accelerated by the spread of diseases—particularly smallpox—prior to the arrival of Pizarro and his conquistadors.