At first, it was the diseases. The lack of immunity. A huge % of Native Americans died from disease before Europeans even settled in. When the Pilgrims landed, and when the Puritans arrived in the Boston area, they found nothing but abandoned villages. The entire Massachusett tribe wiped out by something. Smallpox, measles, who knows. Squanto returned to New England to find his tribe no longer existed. European fishermen did that. The Portuguese were fishing off North America even before Columbus set sail, and bringing their diseases with them. The first really major war between Europeans and Native Americans in what is now the US was New England's King Philip's War, 1675-76. As they had learned in the earlier Pequot War(1637), the English practiced something that appalled the natives, namely total war, burn entire villages, kill every last man, woman, and child. In the attack on the Pequot Fort in 1637, when Narragansett warriors who allied with the English saw what the English were doing, they either fired their guns in the air, or left. Murdering women and the elderly was not part of the game plan when native fought native.