This area was first settled by people of the Saqqaq culture about 4300 years ago, who presumably traveled via Ellesmere Island. A later wave of migration from Alaska via Canada ended in Greenland around 1000 BC and resulted in a more modern settlement of the region surrounding Qilakitsoq. In the time of the Thule culture, which lasted until about AD 1800, a settlement of about 30 residents was located here. They lived as hunters and gatherers; in the winter, they resided primarily in sod houses, while they spent summers living in tents on extended hunting trips in the surrounding fjords. The region was rich in game; in addition to seals and whales, polar bears, reindeer, and rock ptarmigans were probably also hunted. People fished as well.

The first description of Qilakitsoq, which was named "Killekitok" by Europeans at the time, is from 1789, shortly after the founding of the Uummannaq colony (1761). At this time, Qilakitsoq was, much like other similar settlements, only occasionally populated in the winter; this lifestyle is ascribed to the Thule culture of the time and was comparable to the lifestyles of mummies found from around the year 1500. The last description of a permanent settlement in Qilakitsoq was written in 1811. Shortly thereafter, the settlement was apparently abandoned by its native population. A reason for this migration could be competition for food from the newly arriving Europeans, who used nets to hunt seals in large numbers.[1]