One word:
Rifle
Nuff said.
Not necessarily because of the rifle. Many was the time when the Indians had and used a better rifle they bought from the gun-runners. The U.S. Cavalry sometimes fought with a single-shot breechloader against a Plains Indian armed with a breechloading and lever action repeating rifle. In any event, the Amerindian cultures lost their effective control of the real estate long before they set eyes upon the first Old World colonists. Between the constant inter-tribal warfare and the pre-Columbian and post Columbian pandemics,the Amerindian cultures lacked the populations necessary to control the vast and depopulated real estate of the Americas.