Federigo was the son of Agostino Fregoso, governor of Genoa in 1488 for Ludovico il Moro, and of Gentilla de Montefeltro, niece of Guidobaldo, Duke of Urbino.
Fregoso spent his youth at the court of his uncle, the Duke of Urbino, and after taking Catholic orders, received in 1507 from Pope Julius II the Archbishopric of Salerno.
At the court of Urbino, Federigo had received a good classical education, and had allied himself with such humanists as Pietro Bembo and Baldassarre Castiglione.
Three years later, the Fregosi family returned to Genoa, Ottaviano became Doge, and after having become his chief counsellor, Fregoso was placed at the head of the army, and defended the Genoan republic against such internal dangers as the revolts of the Adorni and the Fieschi) as well as suppressing the Barbary piracy.
Being given the command of the Genoese fleet, in which Andrea Doria was serving, Fregoso surprised Kurtoğlu before Bizerta, landed on the island of Djerba and returned to Genoa with treasure.