He fought successfully for King Francis I, alongside the Chevalier de Bayard, in the Italian Wars; in 1547, he acquired the rank of colonel of the mercenary Corsican troops, and, in accordance with usage, became known by his moniker (indicative of his place of origin).
With French and Ottoman support, he landed on the shores of Corsica in 1553, and managed to summon a revolt against the Genoese, defeating the troops of Andrea Doria on several occasions.
However, the French became preoccupied by the ties established between the new English Queen Mary Tudor and Emperor Charles V. Sampiero was recalled in 1555, and a five-year armistice was signed the next year between France and Genoa, in Vaucelles.
Backed by Catherine de' Medici, Sampiero returned to Corsica in 1564, leading a group of Corsicans and Gascon mercenaries.
Although initially victorious in several skirmishes, he was soon left without French support, as well as faced with the indifference of the population and the suspicion of the Corsican nobility (dominant families fled to Genoa).