I think this would have the same issue as an African setting, but to a lesser degree. What part of the area is your setting? Africa is huge and diverse, and so is America. You have to decide which part and culture you are exploring, which might make the game less interesting to some people. Also, much of what we know of these settings is what was reported by colonizers, meaning we knew what these cultures were like after some contact with western culture and seen through western eyes. As an author, you either have to accept this bias, or you have to go on legends and stories that are part myth.
It can be done. Basic DnD did Maztica which I believe is now a part of the Forgotten Realms. I saw a kickstarter for another Central American setting last year. Greyhawk has the Olman, which are very post-colonial even post-apocalyptic take on the Aztec. And i think that is the solution - pick one place and set of related cultures in one historical context, and work with that.
Edit: Necro for life!