In what's now the continental US (and elsewhere, but let's stick with the US for now), the first wave of colonists were vigorously resisted, which is why the likes of Juan Ponce de León, Pánfilo de Narváez, Hernando de Soto, and Lucas Vázquez de Ayllón are best remembered for their failures to establish colonies in La Florida. Just to hit the highlights:

In 1521, Ponce de León ran afoul of the Calusa's shoot-first-ask-questions-later policy regarding the Spanish (likely encouraged by the Taino refugees who established villages under the Calusa's protection after fleeing the Spanish invasion of Cuba). Fatally wounded, Ponce de León retreated from Florida and promptly died. He's rather charitably remembered as the man who led the European discovery of the mainland US, though his attempts to establish a permanent presence there failed.

The same year that Ponce de León died, Lucas Vázquez de Ayllón was organizing efforts to colonize what's now the Carolinas from the Bahamas, a region that was known on Spanish maps in the 1520s as Tierra de Ayllón due to his royal charter on the territory. Men under Ayllón's command captured dozens of Native slaves from the area in order to establish guides, informants, and translators for the eventual colony. Ayllón's favorite was a man given the name Francisco de Chicora (Chicora being the name of his tribe). Chicora traveled with Ayllón to Spain to drum up support for the colony, and in 1526 the two of them, along with 600 others established San Miguel de Gualdape - the first European colony in the continental US. Chicora, now home, promptly abandoned the colony. After three months of dwindling food reserves and persistent indigenous resistance, 150 surviving colonists fled back to the Bahamas. Ayllón was not among them.

Two years later, Pánfilo de Narváez (the same guy who failed to arrest Cortez in Mexico) led another expedition into what's now Florida. Narváez's expedition bypassed the Calusa but was rebuffed by the Apalachee near modern Tallahassee, FL. Afterward, Narváez's ground forces attempted to retreat back to the naval forces on hastily crafted rafts. Narváez's raft was swept out to sea and the conquistador was never seen again. The others went along the Gulf coast until they were shipwrecked in near Galveston, TX. Of the 300 men who made landfall with Narváez, only 86 reached Texas and only four ever reached Spanish territory again. Álvar Núñez Cabeza de Vaca, who spent eight years in Texas before walking the long way to Mexico City, is the most famous of these survivors.

Cabeza de Vaca's report of the American Southeast and Southwest inspired two more expeditions into the current US in the late 1530s through the early 1540s. Francisco Vázquez de Coronado led an expedition into the Southwest, eventually crossing into the Great Plains, guided by Cabeza de Vaca's fellow survivor Estevanico, who died during the Zuni resistance of Coronado. Unlike the other conquistadors here, Coronado had the good fortunate of making it out of his failed expedition alive.

Unlike his contemporary, Hernando de Soto didn't know when to call it quits. Between 1539 and 1542, he marched his men from Florida to North Carolina, and from there westward across the Mississippi, guided in part by a member of Narváez's belated rescue party that had been stranded in Florida. Unlike Narváez, de Soto's men narrowly managed to defeat the Apalachee and secured Anhaica, the Apalachee's principal town, as their base of operations. However, the Apalachee carried out an extensive and successful guerrilla campaign against the Spanish, forcing them out of the town to follow faint hopes of green pastures elsewhere. From there, de Soto's expedition is a cascade of tragedy, for himself as well as the indigenous nations he contacted. He managed to survive for as long as he did based on a combination of dumb luck and paranoia that somehow managed to overcome his hubris and greed. His men kept advising him to pick this territory or that territory as his colony, but de Soto was always unsatisfied and kept leading his men onward on a war of attrition he was losing. Eventually, de Soto died of a fever on the western bank of the Mississippi. After a failed attempt to cross Texas to get back to Mexico, de Soto's men were forced to flee down the Mississippi pursued the vast armada of Quigualtam, whose forces boasted that they would conquer Spain if only they had ships to reach it. It seems that Quigualtam brandished his boastful armada as warning against future attempts at conquests, as they seemed more interested in harrying the Spanish and reclaiming Spanish-held captives than actually wiping out the exhausted expedition completely.

In 1561, the Spanish captured a young man from Tsenacommacah, which the Spanish called Axacan, and we call Virginia today. This man, who was eventually baptized as Don Luis, was a member of one of the communities that were or would soon be part of the Powhatan Confederacy. Over ten years, Don Luis traveled extensively through the Spanish Empire, visiting Mexico, the Caribbean and Spain. In 1570, he was part of a modest effort to establish a colony in Axacan. However, like Chicora before him, Don Luis immediately abandoned the colony and returned to his own people. When the Spanish came to reclaim him, Don Luis led an assault on the colony. Only a single altar boy survived to be adopted by the local community, though he was returned to the Spanish when a Spanish vessel eventually showed up to investigate why the Axacan colony fell off the map.

There's a popular, though dubious, tradition that associates Don Luis with Powhatan himself or, more often, his brother and successor Opachancanough. Certainly, the scant Spanish records concerning Don Luis describe him as the nephew of a prominent leader in the area (based on the laws of hereditary employed in the area, this would have readily put him in the line of succession). Equally certain, Opechancanough is famed for his staunch anticolonial policies. But he had ample reason to resist English colonialism even without prior experience with the Spanish.

Which gets us to the reasons why places like St. Augustine, Jamestown, and Plymouth succeeded were other attempts failed.

Sometime after de Soto's expedition marched through the area, a war broke out between the two most powerful Timucua alliances in northeastern Florida / southeastern Georgia. The two sides both sought out European alliances. The Spanish allied with the dominant Utina; the French allied with the Saturiwa along with other local factions. The Timucua wars and alliances permitted the Spanish to establish a permanent foothold in the area, which resulted in the establishment of St. Augustine. Soon even the Calusa were warming to their Spanish neighbors. The Calusa certepe (paramount chief) known to the Spanish as Carlos likewise sought a military alliance with the Spanish and toward that end, his sister soon married Pedro Menéndez de Avilés, the founder of St. Augustine. The Calusa also began sending trading missions to Cuba. Despite their close ties with the Spanish, the Calusa maintained their autonomy until the English and Creek slave raids into Florida during the early 1700s.

Likewise, Mamanatowick Wahunsunacawh (leader of the Powhatan Confederacy, also known as Chief Powhatan) and Massasoit Ousamequin (leader of the Wampanoag Confederacy) saw the handfuls of English colonists that initially settled in their area as potential military allies and trading partners against more immediate and local enemies. For the Powhatans' this included the Monacan to the west, the Massawomecks and Susquehannocks to the north, and the Spanish to the south. For the Wampanoag, they were almost exclusively concerned about the Narragansett to their west, who had largely been spared an epidemic that had devastated the Wampanoag's formerly sizable numbers (enough that their numbers alone discouraged European colonial aspirations in the area until the epidemic(s) of the late 1610s).

EDIT: I forgot to include Juan Pardo's expedition into the Carolinas during the 1560s. Luckily, I had a chance to mention in here.