The Lewis and Clark journals contain some of the earliest and most detailed written descriptions of a large part of the United States before Euro-American settlement. We used the journal entries to assess the influence of humans on wildlife distribution and abundance. Areas with denser human population, such as the Columbia Basin and the Pacific Coast, had lower species diversity and a lower abundance of large mammals. The opposite effect was observed on the Plains. We believe that overhunting before Euro-American contact and the introduction of the horse, which heightened the effects of hunting, may have been major contributors to the historical absence of some species that are present in the archaeological record. The results show considerable human influence on wildlife even under relatively low human population densities. This finding has major implications for conservation biology and ecological restoration, as human influence is often underestimated when considering presettlement conditions.