Born in Florence, Amerigo studied at the University of Pisa, before becoming secretary to his uncle who was Florentine ambassador to Paris. From 1480 he become an agent of the Megici family of Florentine bankers.

In 1491 they sent him to Serville in Spain to look after their shipping interests there. Thus, he was there when Christopher Columbus sailed upon, and returned from, his first voyage of discovery.

Attracted more by the prospect of going to sea than merely supplying provisions to the ship, he partook in two expeditions to the New World in 1497 and 1499. The second of these discovered Brazil and the mouth of the Amazon river.