Born in Estremadura, Spain, he was of a noble but poor family. He was educated by Pedrarias Davila. At the age of 23, he went with Davila to America. In 1532, he joined Francisco Pizarro in the conquest of Peru.
De Soto returned to Spain with a fortune, was received with honor by the emperor, and married Davila's daughter.
In search of gold and jewels, he undertook at his own expense the conquest of Florida in 1538. He was joined by 600 cavaliers, both Spanish and Portuguese on May 30, 1539 in Tampa Bay. For four years they wandered southeast America searching for treasures. The Native Americans misled de Soto and his men deeper into the wilderness for promises of treasures.
De Soto died on the banks of the Mississippi. To conceal his death, his followers wrapped his body in a mantle, and in the night sunk it in the middle of the river.