Published in 2005, 1491: New Revelations of the Americas Before Columbus was written by Charles C. Mann. A companion work, 1493: Uncovering the New World Columbus Created, was released in 2011. The first chapter introduces many of the problems and inadequacies surrounding popular accounts of native societies. The author describes the tendency to minimize the cultures that existed prior to the arrival of Europeans. Native cultures are seen as simpler and less sophisticated than contemporary European societies. The reason for this, Mann believes, is as much cultural chauvinism and Eurocentrism as it is simple ignorance. This ignorance, Mann argues, creates both positive and negative misrepresentations of the diversity and impact of native civilization.

Chapter 2, "Why Billington Survived" tells the story of Tisquantum, also known as "Squanto," and his aid to the Pilgrims. Mann expands the historical context of Squanto’s story. "Billington"—the surname of a settler and an ancestor of Mann himself—survives only because of Tisquantum's aid to the colony. Mann's account of this aid provides the political significance behind Tisquantum's act, as well as how his own personal story influenced his motives. Mann highlights how traditional accounts of the story tend to ignore the convoluted politics of the tribes of the region, as well as Tisquantum's own complex motivations.

The third chapter of 1491 describes the dramatic rise and fall of the Inca Empire. Throughout the chapter, Mann emphasizes the "imperial" character of the Inca—the centralization of rule, their incorporation of different cultures and communities, and the sheer scale and scope of their territory. The Inca are, to Charles Mann, an empire akin to its contemporaries in Eurasia. Chapter 3 describe the meteoric rise of the Inca over the 15th century, its leaders (each titled "The Inca"), and their conflicts and contributions. The arrival of Pizzaro and the down of the last Inca emperor, Atawallpa, coincides with what the author identifies as a particularly precarious moment in the Inca Empire's history: a succession crisis at a moment of high centralization.

In Chapter 4, "Frequently Asked Questions", Mann focuses on the Aztec Empire, and the arrival of Hernán Cortés in 1519. Following the history of the Mexica and their rise to prominence in the Triple Alliance (also known as the Aztec Empire), Chapter 4 presents the city of Tenochtitlan as a vast metropolis, the likes of which Cortés and the conquistadors had never seen. The story of Cortés's dramatic siege of Tenochtitlan, however, is overshadowed by another phenomenon: an epidemic that ripped through the territory of the Triple Alliance, decimating the native population. The author combines the disease hypothesis for this epidemic with two others: a high level of centralization, and a wealth of unhappy, ambitious neighbors. These factors, in Mann's view, make these large empires susceptible to toppling by outside powers.

The fifth chapter of 1491, "Pleistocene Wars," addresses hypotheses of the genetic and geographic origins of Native American peoples. The chapter discusses a popular hypothesis in anthropology and archaeology, which suggests Native Americans crossed from Eurasia to the Western Hemisphere over a land bridge between modern-day Kamchatka and modern-day Alaska. The chapter describes the sampling of mitochondrial DNA from native populations, and its genetic proximity to Siberian populations. Further, climatology studies reveal possible intervals over which passage was possible.

Chapter 6, "Cotton (or Anchovies) and Maize," describes the importance of certain agricultural products for native civilizations, some contrary to conventional expectations. For example, in Peru, the predominance of cotton and maize is accompanied by the importance of fishing; this strong maritime influence goes against conventional accounts of how ancient societies were expected to develop. Chapter 6 also gives a sociopolitical explanation for the erection of monuments, as local powers and institution accrue enough strength and security to support these large-scale projects.

The basis of Chapter 7, "Writing, Wheels, and Bucket Brigades," addresses the role of technology in early Mesoamerican society. The focus of this chapter is why some developments were absent or unapplied in Mesoamerica—such as the wheeled cart—while others, such as writing, developed in ways contrary to that in Eurasia. Mann's explanation looks first at the geography of Mesoamerica, which is difficult—even now—for wheeled transport, before discussing how social need drives invention. The wheel was not an unknown concept, as toys and trinkets from Mesoamerica show; rather, it’s that they were a technology unapplied. Meanwhile, contemporary mathematics were highly sophisticated. The author provides a cultural explanation for this: the emphasis on calendars and record-keeping in Mesoamerica reflected a focus on that cultural concept, given the religious beliefs of the region's societies.

The main argument of Chapter 8, "Made in America," is a challenge to the "Pristine Wilderness" myth. This central idea contained in the Pristine Wilderness myth is that the landscape of the Americas was largely untouched prior to the arrival of Europeans on the continent. Instead, Mann argues that native societies and civilizations had a large influence on the land, actively reshaping the environment to their needs. The chief tool of this, Mann explains, was fire. Fire gave native populations a level of control that allowed them not to make sweeping changes to the landscape. However, Mesoamerican land cultivation was not foolproof: special climactic conditions, such as drought, or the overdevelopment of land could have disastrous consequences for communities, regions, and even entire civilizations.

Chapter 9, "Amazonia," centers on the environmental adaptations made in the Amazon rainforests. The historical backdrop of this discussion is an account by Gaspar de Carvajal, a Spanish explorer who reported the Amazon to be a densely-populated region. Chapter 9 examines the use of "slash-and-burn" agriculture as a way of enriching soil, and the development of terra preta, a sought-after type of Amazonian soil. Contrary to conventional ideas of agriculture, the author cites a groundbreaking work by anthropologist Betty Meggers, who claims that the soil itself is an agricultural product; after hundreds of years of preparation, the soil is especially prepared to raise the crops needed by these communities, though only in relatively small amounts.

In Chapter 10, "The Artificial Wilderness", Mann addresses possible objections to claims made earlier. Specifically, Mann looks to contextualize accounts by Francis Drake and Hernando de Soto, among others, whose journals and reports were the basis of the "pristine wilderness" myth. The author's argument is that these explorers and conquistadors were not mistaken in their accounts, but were witnessing a large-scale ecological anomaly, brought indirectly about by recent pandemics. These pandemics, which counter-intuitively preceded the establishment of European colonies and settlements, disrupted native society and their ability to control their environments,, and led to uniquely "pathological" conditions: giant herds of buffalo and deer, flocks of passenger pigeons. As spreading disease wiped out entire communities and societies, nature essentially reclaimed the land—a phenomenon the Europeans were able to witness first-hand.

The final chapter of 1491, "The Great Law of Peace," discusses the cultural and social impact of native civilization on the European—and, later, Anglo-American—societies that replaced them. The author's argument is that the notions of liberty and egalitarianism that animated these new nations were inspired by Europeans' contact with the alternate social structures that existed in the New World. While the structure of the Five Nations in the New England region seems to be an early model for consensus-driven, representative government, the theory is difficult to prove elsewhere on the continent. As the author himself shows, native society was politically-diverse, with examples as imperial and hierarchical as any of their European contemporaries. Mann illustrates in the final chapter of his book that something of the character of these "lost" civilizations continues to persist within our own.