Reading James Wilkinson's recent bio, he was in command of the U.S. Army and dithering about Spanish Louisiana since he would have directly been dealing with the Spanish Army in New Orleans (and was spying for them at the same time as well as the French and Aaron Burr's personal empire scheme.) He didn't think the American forces could readily overcome the Spanish (and had briefly been the Continental Army's head quartermaster, incompetently, but had a good sense of the Americans' difficulties of supply and reinforcement compared to the Spaniards' resupply in New Orleans from Cuban and Mexican bases.
The question would be what Spain did with Spanish Louisiana until the American settlements were well past the Appalachian Mountains and it's Army and Navy much larger. By 1807 Moses Austin was already in St. Louis and probably thinking about his real estate development schemes in Spain's nearly empty lands that would culminate in he and his son's Texas colonization and that nibbling by American colonists and filibusters would probably be the fate rather than a major war neither could staff or supply in the Mississippi Valley.
To have a different fate for Spanish Louisiana, you'd have so many POD's:
A. Smart governance of that colony unlike most of their others that developed the economy, drew hundreds of thousands of immigrant settlers (Spanish, Irish Catholics, Austria-Hungarians, Italians, German Catholics?), focused on building cities and towns instead of vast plantations and ranches like everywhere else for indefensible results, implemented new technologies like river steamboats, telegraphy, common stock companies, insurance, canal-building, sugar refining, etc. immediately, and kept 20-40,000 soldiers based along the Mississippi to match or exceed the U.S. Army...it could work out. Oh and treat the Indians far more smartly than anywhere else in the Spanish empire so instead of quickly dying off slaves or fugitives, they were friendly proxy armies (like the French relied on in North America) and key providers of both foodstuffs (corn, cotton, squash, beans, pumpkins, dried meat) and salable goods (beaver fur, buffalo hides, deer hides, etc.). The Spanish did understand and focus on mining more than many empires so the Michigan copper, Michigan-Minnesota Mesabi Range high quality iron ore, Missouri's iron and lead mines (just being opened up in the 1800-1830 era), Illinois coal, and the many gold and silver deposits Spanish expeditions had already found and often mined throughout the West. That would have lured settlers just as Iowa's flat 40" deep topsoil did but the Spanish model was unusually inept at drawing productive settlers so a nearly empty, indefensible place nibbled away at the borders over the 19th century seems more likely a fate.