He was the son of Pierfrancesco di Lorenzo de' Medici, and therefore a member of a secondary branch of the family.

They conceived a passion for classical studies and books, and later created a large library of manuscripts and codexes.

The following November, Lorenzo and Giovanni returned to Florence in the wake of Charles VIII of France's invasion of Italy, as Piero had been ousted by a Republican revolution in the city.

Their support for Girolamo Savonarola gained them the Popolano ("commoner", "plebeian") nickname.

Giovanni il Popolano died on 14 September 1498 in Santa Maria in Bagno, Papal States, aged 30.