[1]: 7 Piero was educated to succeed his father as head of the Medici family and de facto ruler of the Florentine state, under figures such as Angelo Poliziano or Marsilio Ficino.

After a brief period of relative calm, the fragile peaceful equilibrium between the Italian states, laboriously constructed by Piero's father, collapsed in 1494 with the decision of King Charles VIII of France to cross the Alps with an army in order to assert hereditary claims to the Kingdom of Naples.

[5]: 184 Piero attempted to mount a resistance, but received little support from members of the Florentine elite who had fallen under the influence of the fanatical Dominican priest Girolamo Savonarola.

[5] By the end of October, Piero had not succeeded in gaining any support for Florence, and, without consulting the governing Signoria, decided to visit Charles at his camp and try to win his friendship.

During their meeting, Piero acceded to all of Charles's demands, including surrendering the fortresses of Sarzana, Pietrasanta, Sarzanello, and Librafratta, as well as the towns of Pisa and Livorno.

[5]: 186 When Piero returned to Florence to report back to the Signoria, he was greeted with public outrage, and he and his family fled the city for Venice.