By the early 1530's, De Soto was known as an excellent soldier and horseman. He joined an expedition led by Francisco Pizarro, against the empire of the Inca Indians in what is now Peru. After a short delay, the men began their journey in 1532 with a small army of 168 men. They reached the city of Cajamarca, where a huge Inca army, commanded by Emperor Atahualpa, was camped.

Pizarro sent De Soto with a small troop of fifteen calvarymen to invite Atahualpa to meet with Pizarro. The Spainards ambushed the Inca and captured their emperor. Although the Inca paid an enormous ransom for their emperor, the Spainards carried out the execution. De Soto helped Pizarro capture Cusco, the Inca's capital, in 1533.

in 1536 De Soto returned to spain a rich man from treasures collected during the Inca conquest. He took a wife and went on to lead a noble lifestyle. Eventually he sought his own command in the New World. King Charles I of Spain appointed him governor of Cuba and authorized him to conquer and colonize the region that is now the southeastern United States.

Journey to the Mississippi- Se Soto arrived below present day Tampa Bay in 1539. He brought more than 600 men to help colonize the land and search for gold. His plan was to capure Indian chiefs and take Indians as ransom.

The army camped for the winter in what is now northern Florida and headed north during the spring and summer of 1540. Subsequently, making their way back south in the area that is now known as Georgia and Alabama. In October of 1540, followers of the Choctaw leader Tuscaloosa ambushed De Soto's army at the town of Mabila, south of present day Montgomery. Despite emerging victorious, De Soto's army retreated northward, where he discovered then crossed the Mississippi River.

On May 21, 1542, De Soto died from a fever, possibly from a war related injury by the banks of the Mississippi River. The remains of his army, led by Luis De Moscoso, reached New Spain (now Mexico) the following year.