The peopling of the Americas began when Paleolithic hunter-gatherers (Paleo-Indians) entered North America from the North Asian Mammoth steppe via the Beringia land bridge, which had formed between northeastern Siberia and western Alaska due to the lowering of sea level during the Last Glacial Maximum. These populations expanded south of the Laurentide Ice Sheet and spread rapidly southward, occupying both North and South America, by 12,000 to 14,000 years ago. The earliest populations in the Americas, before roughly 10,000 years ago, are known as Paleo-Indians. Indigenous peoples of the Americas have been linked to Siberian populations by linguistic factors, the distribution of blood types, and in genetic composition as reflected by molecular data, such as DNA.

The genetic history of the Indigenous peoples of the Americas is divided into two distinct periods: the initial peopling of the Americas during about 20,000 to 14,000 years ago, and European contact, after about 500 years ago. The first period of the genetic history of Indigenous Americans is the determinant factor for the number of genetic lineages, zygosity mutations, and founding haplotypes present in today's Indigenous American populations.