Although in 1539 he married another Medici, Laudomia di Pierfrancesco, he was a fierce opponent of the main line of that family. He fought in the army led by his father and other Florentine exile from France to oust the Medici from Florence, but, after their defeat at the Battle of Montemurlo, Piero fled to France at the court of Catherine de' Medici.
He was named marshal of France in 1554.
Later he fought in the defence of the Republic of Siena against Cosimo de' Medici, leading a French army. He obtained a pyrrhic victory at Pontedera on 11 June 1554, but his army could not receive help from the ships of his brother Leone (who had been killed by an arquebus shot near Castiglione della Pescaia) and he was forced to retreat to Pistoia. On 2 August his defeat at the Battle of Marciano meant the end of the Senese independence.
He is generally credited as the inventor of the dragoon military speciality (arquebusiers à cheval or horse arquibusiers).
His son Filippo was also a military commander.