During the lifetime of his father, Cosimo de' Medici, he did not play an extensive role due to his perpetual poor health, the source of his nickname. He was the last Medici elected to the office of Gonfaloniere, however, in 1461.
Upon taking over the family 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 and Niccolò Soderini, using troops provided by Borso d'Este, the Duke of Ferrara, and commanded by his brother Ercole d'Este. Piero was warned by Giovanni 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 his father; 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 Bartolommeo Colleoni. Thereafter Piero's rule was secure, although he did little of note.
He also continued the family's tradition of artistic patronage, including Botticelli's Adoration of the Magi, and Gozzoli's fresco Procession of the Magi. (In both of these one can see 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 Verrocchio commissioned by his sons Lorenzo and Giuliano.