I'm going to outline something of a Spain wank that has various factors coming together to create an incredibly prosperous Spanish Empire. Any of these things should be a positive for the general wealth and power of a state based in the Iberian peninsula:
A more meritocratic administration of the New World both free of the Spanish caste system and one that tries to integrate the natives into the Spanish fold(more than they already were) would go a very long ways to creating a healthier Spanish economy(in the sense of Spain and her New World colonies).
Ignore Europe completely north of the Pyrenees, sign a formal treaty with France that declares the New World in its entirety to be Spanish and that Spain and France will stand in perpetual friendship to each other. In exchange, France has the right of tariff free trade in continental Spain and access to any and all New World goods at more competitive prices than any other European state.
Don't depopulate Castille in order to settle the New World, instead draw from other continental European holdings for settlement into provinces that are already Spanish-speaking. Draw from non-Spanish subjects when possible. Rely on Spanish speakers from both the Old and New world to settle new frontiers.
Ensure naval supremacy and the complete disarray of England at all costs; burn their colonies, oppose their trade missions, fund pretenders, sabotage any outre-European expansion by the English.
Fuck the Pope and ignore the reformation. Better yet embrace it and tear down the notable drain on the Spanish economy that monastic life resulted in in Iberia. Do not break commercial ties from Lisbon to Antwerp; encourage commercial missions by these individuals under the Crown much like the settlement of Madeira.
If you're going to pursue dynastic marriages pursue them with the French and the Italians; being tied down anywhere else is not going to result in anything positive for the Iberian peninsula beyond a breaking of the Spanish-French alliance.
If the Iberian Union forms either due to it being imposed or through Miguel Da Paz or some other occurrence, make Portugal as integral to the crown as possible.
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The above would result in a far more populous Spain that has been free of invasion for centuries with France as the Great Blue Buffer, has complete suzerainty over the New World, dominates the spice trade, and likely has a far more developed economy than it's OTL equivalent.