One of the main themes of 1491 is upending the idea that prior to the arrival of Europeans, the Americas were an undisturbed wilderness. This theme is an example of Eurocentric narratives that underestimate and de-emphasize the abilities of the Native civilizations encountered in the Americas. This theme originates from Europeans neglecting portions from the early accounts of conquistadors and explorers that spoke to the high population density of these communities, while favoring latter accounts, which stated that population density was low and that Native cultures did little to harness the land. Mann argues that this assumption is based on ignorance of the ecological effect of the pandemics that scourged the Americas in the years prior to European colonizers encountering Native cultures. Mann refutes the idea that natives did not alter their environments by pointing to the extensive ecological manipulations brought by large-scale crop engineering and slash-and-burn techniques of agriculture—techniques that were disrupted by the pandemics that devastated these societies.

For Mann, this theory has differing ideological motivations. On one hand, the "virgin soil" theory minimizes the effect of native civilization. By trivializing the effect that Native societies and civilizations had upon their environment, and instead leaning on an image of indigenous Americans as hunter-gatherers, this theory minimizes the sophistication of Native societies.