To understand the next part of this thing we call American history, one first has to understand the Iroquois. Unlike many of the other groups of peoples in pre-Columbus North America, tied together by common origins of language, the Iroquoian peoples were relatively new on the scene, not really emerging as distinct culture and language along the Saint Lawrence River until around the twelfth century. Exactly how this took place is unknown, though some stories suggest they were originally slaves of the Algonquian peoples in the area who broke free, creating their own culture. Like many of the Algonquian peoples along the eastern seaboard, the Iroquoian were a much more matrilineal culture, meaning things like property and lineage were passed down via mothers rather than fathers, an arrangement that gave women a significant amount of power, though men still tended to dominate leadership and religious roles. However, the Iroquoian languages are more closely related to Siouan languages than Algonquian languages. As well, the Iroquoian differed in that they had a much more fluid concept of what it meant to be part of a group. While the Algonquian tended to view themselves in terms of specific tribes and villages, the Iroquoian saw themselves more in terms of shared collectives with shared beliefs.
This penchant for collectivism not only made it easier for the various Iroquoian peoples to form complex alliances with each other, it also allowed them to grow in strength rapidly. One did not have to be born Iroquoian to become Iroquoian, and those captured in raids or through other means quickly found themselves able to assimilate and become full members of the group. Thanks to this, over the next several centuries the Iroquoian peoples grew greatly in numbers, soon dominating the entirety of the shores of the Saint Lawrence River.
The decline of the Mississippi culture in what is today the Southeast and Midwest coincided with a rapid Iroquoian expansion in the fourteenth and fifteenth centuries. Pushing south and west from their ancestral homelands, they moved into the eastern Great Lakes and upstate New York and Pennsylvania. This of course did not sit well with the Algonquian tribes living in those areas. Being too divided to put up a strong enough resistance, they instead moved westward into the Midwest, in turn displacing many of the Siouan peoples and hastening the end of the northern half of the Mississippi culture. Some of the more aggressive Iroquoian groups even pushed their way significantly more southward, becoming several scattered groups in the southeast, the most dominant being the Cherokee.
Due to such a rapid expansion, the Iroquoian peoples begin to lose much of their cohesion, leading to conflict amongst themselves even as they pushed deeper into the interior. This loss of cohesion and increase in conflict was somewhat reversed starting in the mid-fifteenth century via the creation of several complex alliances amongst various tribes. The most powerful of these were the Iroquois Confederacy in upper New York, the Huron Confederacy to the north along the eastern Great Lakes, and the Susquehannock Confederacy in upstate Pennsylvania. Though these alliances became dominant political powers in the interior, the greater number of Algonquian peoples along the Atlantic Seaboard limited the influence of that power towards the coast.
The arrival of Europeans to the New World at first had little affect on the Iroquois, at least until some schmuck named Hernando de Soto wandered across the southeast between 1539 and 1542, sparking a horrifying pandemic which spread north into the Midwest, devastating the Siouan peoples there. As a result, the Algonquian living in the interior began to quickly spread south from the Great Lakes and west from the Appalachians, which in turn made it easier for the Iroquoian to spread westward into the Great Lakes region, which in turn drove more Algonquians to move into the Midwest, pushing the surviving Siouan peoples out onto the Great Plains, where they in turn beat the shit out of the local Numic peoples, who were just doing their best to survive in barren lands historically nobody else wanted. It was a real cluster fuck, one that only got worst when the English, Dutch, and French began to arrive in North America at the start of the sixteenth century.