During his father's life he did not play an extensive role due to his perpetual poor health, the source of his nickname, which he inherited from Cosimo. He was the last Medici elected to the office of Gonfaloniere, however, in 1461.
Upon taking over the family Medici bank from his father, Piero had a financial overview prepared; the results led him to call up a number of long-standing loans, many to various Medici supporters, which his father had let stand. 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, using troops provided by Borso d'Este, Duke of Modena and Reggio, and commanded by his brother Ercole d'Este (planned for August 26, 1466). Piero was warned by Giovanni II Bentivoglio, and was able to escape the coup, in part because his son Lorenzo discovered a road-block set up by the conspirators to capture Piero in his trip towards the Medici villa at Careggi; he was not recognized, and was able to warn his father. The coup failed, as did an attempted repeat backed by Venice, using troops commanded by Bartolomeo Colleoni.
In 1467 he had to face the war against the Republic of Venice, prompted by the Florentine support given to Francesco I Sforza, the new duke of Milan. However, the Venetian army under Colleoni was defeated at the Battle of Molinella by the league of Florence, Naples, Papal States and Milan.
He also continued the family's tradition of artistic patronage, including Gozzoli's fresco Procession of the Magi (in which are also present both of Piero's sons, Lorenzo and Giuliano, as well as Piero himself). His taste was more eclectic than that of his father, extending to Dutch and Flemish work.
He also continued to collect rare books, adding many to the Medici collections. Although not as brilliant a banker as his father, he was able to keep things running smoothly during his tenure.
He died in 1469, due to gout and lung disease, and is buried in the Church of San Lorenzo, next to his brother Giovanni; their tombs are decorated with a statue by Andrea del Verrocchio commissioned by his sons Lorenzo and Giuliano.