In this book, Charles Mann is arguing that the societies of the Americas in pre-European contact times were much larger and more sophisticated than we tend to think. He is arguing that the coming of the Europeans destroyed something that was rather special. He argues that the Europeans destroyed Indian society both on purpose and accidentally. The “worst thing” that De Soto did, he says, is one of the accidental things.
To be precise, Mann is not saying that he believes this is the worst thing that De Soto did. Instead, he is saying that other people think it is, but is not arguing that they are wrong. The worst thing, in this view, was bringing pigs to the Americas. As Mann says on the first page or so (I have this on Kindle with no page numbers) of Chapter 4, De Soto
...managed to rape, torture, enslave, and kill countless Indians. But the worst thing he did, some researchers say, was entirely without malice—he brought pigs.
According to Mann, pigs were the reason why De Soto found large numbers of villages and a dense population whereas the next Europeans to come by, more than a century later, found a very sparse population. Mann says the pigs, some of which escaped the Spanish and started to breed, carried diseases that decimated the Indian population.