The Wyoming Valley prior to the arrival of Europeans is impossible to entirely reconstruct. Inferences and speculation based on the archaeological record constitute most "knowledge" of this period. To further complicate matters, the archaeological record of the region is severely damaged and largely lost due to the region's coal mining past. Nevertheless, an attempt at reconstruction is a necessary and worthwhile exercise, even if much is left to be desired.
Prior to 1550, the Wyoming Valley, it seems based on the archaeological record, was home to native settlements. It has been speculated that the Seneca, Oneida, Lenape, or perhaps Susquehannocks could have been original inhabitants of the land dating back centuries. However, this is, given the available evidence, nothing more than speculation. What can be asserted factually is that there were people or peoples who inhabited the region in small numbers prior to 1550, but their identity will remain a mystery unless breakthroughs in archaeology occur.
Between 1550 and 1675, the archaeological record goes cold, showing no signs of permanent native settlements in the region. A posited theory as to why the area suddenly saw a population decline is that the Susquehannocks and Haudenosaunee, or Iroquois Confederacy, were warring. It is possible that Susquehannocks inhabited some land north of the Wyoming Valley and at some point in the 16th century migrated southward. This migration would have went straight through the Wyoming Valley devastating whatever small settlements they encountered along the way. However, this is mere theory and not fact. Two somewhat simple alternative theories could help to explain the lack of permanent settlements. The first - simply that the archaeological record is under-constructed or simply so damaged by coal mining that the time period will forever be a mystery. The second - that European arrival along the eastern seaboard brought increased opportunities for trade for native peoples, thereby drawing inland peoples closer to the sea to capitalize on such opportunities. It would be extremely likely that a group of people living in the Wyoming Valley would be members of a nation that also had people living closer to the sea in present day New York and New Jersey. Joining their kin in the east could have been a politically and economically smart decision. Of course, the devastation brought by European diseases and the heightened possibility of war could have also played a part in migration eastward. Reinforcing populations in areas hit hard by colonization so that they could maintain control of the land and continue to participate in their economic relationships would have likely been priorities for native nations.
It is important to note, however, that this period of vacancy is not a true vacancy. The Wyoming Valley was not virgin soil upon European arrival. Such a suggestion would be a grave misunderstanding. The Wyoming Valley merely lacked permanent settlements during this period according to the archaeological record. Native peoples still migrated through the area, likely setting up camp for short periods of time while they were on the move as many native peoples were migratory peoples. While the Wyoming Valley might not have been a place of primary settlement from 1550 to 1675, it was certainly a place known to and used by native peoples, as well as a place that nations undoubtedly claimed as their own.