> Didn't the Spanish show up briefly, then come back in force later?

The end of the Incan empire is a really striking example of this dynamic. The Spanish landed on the South American mainland in ~1524, European diseases started spreading, and in 1527 the Incan emperor died from one of the diseases without an heir. This triggered a really brutal civil war of succession that weakened the empire. The Spanish started the conquest proper of the Incan empire in ~1532 and were successful in part because how weak the empire was after the civil war.

So essentially, by arriving early and (inadvertently) initiating the disease epidemics, the Spanish put in place conditions that made the conquest possible a few years later.