On February 23, 1512, Ponce de León received approval for the expedition, making him Adelantado and granting him civil and criminal jurisdiction over all the territories he explored for the rest of his life. Like most of these grants, he was expected to pay for the expense of the venture with no help from the King. Although the King would receive his Qinto (fifth) and other benefits from any treasures discovered.

Diego Bermudez, was the captain of the flagship, the caravel Santiago, and Antón de Alaminos as chief pilot and navigator. Bermudez had the distinction that his brother discovered the island of Bermuda, which was named after him. Alaminos claim to fame, was that he had been a cabin boy on Columbus' first trip to the New World. Besides Bermudez and Alaminos, the crew consisted of seven sailors, 8 cabin boys, and three soldiers.  Juan Buono de Quexo, an old friend of Ponce de León was in command of the caravel Santa Maria de Consolación. This ship contained about thirty-eight persons. There was one women on this ship, Juana Ruíz, who would be the first European woman to set foot on Tierra Firma, of what is today, the United States of America. There were also two free Black Africans on the crew. As part of the party, there were two Indian slaves that were from the Lucayas, (the name given to the present day Bahamas Islands) and would be used as pilots and translators and one white slave. The third ship, the San Cristóbal, was a two mast brigantine of shallow draft allowing it to get close to the shore, under the Juan Perez de Ortubia and probably held about 15 persons. The first two ships were owned by Ponce de León, and the third, was requisitioned with the owners paid for the use of the ship. This ship normally sailed between Española and Puerto Rico, carrying supplies and passengers. In all, there were about 65 members of this expedition, designed to explore and not settle the newly discovered lands.

The ships sailed to the northwest, and skirted the Caicos and Turks Islands. They stopped at Guanahani (San Salvador), where Columbus first made land fall, during his first voyage. They sailed past Great Abaco Island and anchored in eight fathoms of water off an uncharted coast. The next day, they rowed ashore and took of the land in the name of Spain. He found the land very rich in plants, (cypress, jasmines, pines, azaleas, etc) and animals, (birds, turkeys, alligators, deer, etc). Ponce de León made his discovery of Florida during Easter, and because of this, he named the land, Pascua Florida. Ponce de León, believed that the land was part of a large island, and did not know that they were on Tierra Firme. Using antiquated instruments, a astrolabe, they determined that they were at 30º North latitude. This would put them just south of the mouth of the St. Johns River near St. Augustine.  Some scholars believe that this charts were wrong, and place his landing somewhere around Daytona Beach and New Smyrna Beach.

Along the coast, the Spaniards were very interested in learning about the natives in the area. At one point, they came across natives on the beach. The natives signaled them, making them believe that they wanted to meet, and the Spaniards sent a boat to shore. As they approached the shore, the natives attacked the boat, with spears and arrows. Two of the crew were wounded before the Spaniards were able to retreat. At a point near Jupiter Inlet, they dropped anchor and were able to collect fire wood and fresh water. They stayed there, waiting for the lost ship, to rejoin them. While there, another party of natives attacked, but this time they were able to capture one of them, which Ponce de León hoped to teach Spanish to use as a guide and interpreter.

They rounded the Florida cape on May 8^th and encountered a very strong current, causing Ponce de León to name the area, Cabo de las Corrientes. During the next week, they sailed past a string of island, that he named Los Martires because the protruding rocks resembled agonizing men. The trip around the keys, proved very difficult, due to the shallow waters. This required that they have a man, continuously taking soundings, as they went. During the night, they were forced to anchor, for fear of running aground.

In the Marquesas Key, they saw some Calusa Indians that approached them in dugouts, wanting to trade. The Indians had animal skins and guanin (a mixture of gold and copper, that was used by the natives to make jewelry). The Spaniards were surprised to find one of the natives speaking Spanish (he had learned Spanish from either a slaver or some shipwrecked sailor, washed up on the shore). The natives eventually got upset with the trading and grabbed the anchor chains and tried to tow the ships away. During the ensuing battle, the Spaniards were able to capture four of the Calusa women. They told the Spaniards that their cacique, named Carlos, had large quantities of gold for sale.

Continuing north, along the west coast of Florida, as per the instructions of the captive women. On July 11^th, at Charlotte Harbor, the encountered Carlos with his warriors in 80 dugouts, heavily armed with bows and arrows and no gold. The two forces, kept a sufficient distance, so that they could do no harm to each other. 

They continued north for another three days, before they turned around. They headed west and reached the Dry Tortugas, where they found a large amount of wild life. They killed 160 sea turtles, manatees, and thousands of birds (pelicans and gannets). Following the instructions of one of the captives, they turned east, toward the Bahamas. In the Bahamas, the ship that had given them so much trouble, was now suffering from the effect of the teredo worms (Sea worms that are the plague of wooden boats. They will bore through the wood and cause the boat to leak, like a sieve), and foundered on one of the reefs. The crew and settlers were rescued by the other two ships.

Here, Ponce de León decided to return to Puerto Rico in the Santiago. He ordered Ortubia and Alaminos to continue the search in the Santa Maria, for this wonderful fountain of rejuvenating water, which he had failed to find. He had tasted sweet waters at different springs in Florida, but never the right one. Seven months later, on October 12^th, 1513, he arrived in Puerto Rico. In February, 1514, the Santa Maria arrived in Puerto Rico. They were unsuccessful in finding the legendary fountain, but did discover the Island of Bimini.