This immediately drove a good number of the merchants involved into bankruptcy and added to the ranks of those who opposed the Medici.

His time as leader of Florence was marked by an attempted coup led by Luca Pitti, Niccolò Soderini, Diotisalvi Neroni, Angelo Acciaiuoli and his cousin Pierfrancesco de' Medici, who used troops provided by Borso d'Este, Duke of Modena and Reggio, and commanded by his brother Ercole d'Este, planned for 26 August 1466.

It has been argued[4] that the "coup" was in fact a legitimate attempt to limit the power of the Medici faction and restore a system of government in keeping with Florence's traditional republican ideals, and that to refer to it as a "coup" or a "conspiracy" legitimizes Piero's de facto and hereditary (but wholly unconstitutional) status as leader of the city.

In 1467, Piero had to face a war against the Republic of Venice prompted by the Florentine support given to Galeazzo Maria Sforza, the new duke of Milan.

However, the Venetian army under Colleoni was defeated at the Battle of Molinella by a league of Florence, Naples, the Papal States and Milan.

[2] All his family is likely portrayed in the famous painting by Botticelli known as the Madonna of the Magnificat, in which Lucrezia Tornabuoni appears as the Virgin Mary.