People have done a good job covering some of the key cornerstones of a plurality of American Indian Americas; keeping the Europeans out of the established states of Mesoamerica and the Andes, restricting them to malarial lands, etc.
I think something people overlook with respect to New world colonialism or even European overseas expansion is how much of that motivation was driven by someone first setting the example and making it look sexy. Without Portugal's naval developments such as the creation of the caravel and the discovery of the Volto De Mar, I don't think Europeans would have been messing about past the Canaries for at least a century. Who's going to have space, motivation, and opportunity to discover what Portugal did if not Portugal? The English were busy trying to be a continental power, the Scandinavians had already done the big thing then promptly cast it aside as irrelevant, the Irish aren't in a position to do it, the French have to deal with the English before they can even consider becoming a naval power at all, and the other Iberian states were land or Mediterranean powers and focused on what they viewed as their god-given mission to their south against Islam or ambitions in the Western Mediterranean.
The idea goes the same way for Castille's adventures in the New World with conquistadors. If Spain didn't conquer not one but two New World empires and had mountains of silver to show for the effort, would other Europeans have ever thought overseas expansion was worth their while? Hell, I'd go so far as to say that if the Spanish got clapped to a man by Aztec and Cortez's entire expedition died, then the Spanish would have tucked tail and all but the craziest conquistadors would have shied away from trying anything again, maybe even from on top-down by the Spanish monarchs themselves due to it being a big waste of resources. What gold there is in the New World would have been confined to what they found in Hispaniola and what they can finagle in trade with the Mesoamericans but on far more even terms than OTL's extraction colonialism and exploitation of the local people.
If all the Spanish had to show for their efforts in the New World is a few unprofitable colonies in the Caribbean and a tenous trade relationship with the Aztecs that proves somewhat profitable but isn't the fountain of bullion from OTL, then who's really gonna care all that much to replicate them? You'll never know what you don't have unless you go for it and without motivation to go for it, Europe will never know. At best you'll see overseas exploration be seen as a thing for merchants, but having the cajones to try for military conquest goes away for a long time. And with the only profitable trade to be seen existing on the Caribbean rim, you could have attempted settlement in more hospitable lands like the Atlantic Seaboard or the Rio de La Plata not come up for ages because the initial voyages in search of trade found nothing worthwhile and these lands becoming disregarded as worthless and empty.
What I'm getting at is that people lack imagination or understanding of what drove Europeans to the New World. No one knows the results of population growth via settler colonialism, the resources they'll need for industrialization in 300 years, or the value of soft power in the modern era fueled by a shared language.
A more trade-centric mindset to the Americas, or even just butterflying an independent Portugal would wreck world history as we know it and the New World peoples would be far, far better off for it.
