He was born in Piombino, the son of Iacopo III Appiani, of whom he continued the traditional alliance with the Aragonese court of Naples.
Later he served the king of France and Ferdinand II of Aragon.
In 1501 his territories in southern Tuscany were occupied by Cesare Borgia, but Iacopo returned in 1503 after the death of Borgia's power protector and father, Pope Alexander VI.
In this period he received Leonardo da Vinci in his court.
In 1509 he was made Prince of the Holy Roman Empire.