Born in 1519 by Giovanni de 'Medici, called delle Bande Nere (killed in 1526 in a clash with lansquenets), and Maria Salviati, unexpectedly inherited the title of duke of Florence in 1537, at the death of his predecessor Alessandro de' Medici, murdered by his cousin Lorenzino. Faithful to Emperor Charles V, in 1539 he married Eleonora de Toledo, daughter of Pedro de Toledo, viceroy of Naples, and sister of Fernando Alvarez de Toledo, duke of Alba. The action of Cosimo favored the progressive dissolution of the ancient municipal institutions and the state evolved more and more towards a monarchical structure on the model of the great foreign monarchies. This was not forgiven by the Republican opposition, prematurely crushed in the battle of Montemurlo (1537), but that, under the military leadership of Piero Strozzi, gave rise to a long resistance and anti-democracy propaganda at least until the fall of Siena and then last stronghold of Montalcino. In 1554-55 he besieged Siena with the Spaniards, who, once conquered, was annexed to his State with the approval of Philip II.
In the forties and fifties of the sixteenth century Duke Cosimo led an anti-papal policy and was in the odor of heresy (protecting various heretics, including Pietro Carnesecchi, not to mention the frescoes commissioned in Pontormo in San Lorenzo from 1548; Toledo itself was suspected of valdesianism, and even the secretary Pier Francesco Riccio, a powerful court butler, was suspected of reformed sympathies: his relations with the papacy were mostly very tense: Paul III threw the Interdetto against him because of his opposition to the heavy taxes required by the pope to finance the wars against the Turks and Protestants, even more Cosimo was fiercely hated by an intransigent pope like Paul IV, who also considered heretics Charles V and Philip II, allies of Cosimo. 'beginning of the' 60s, particularly since 1562, Cosimo decidedly aligned to the Counter-Reformation, yielding also on the extradition to Rome of Pietro Carnesecch i, previously protected by him, requested by Pio V.
Between November and December, 1562, he lost two of his sons and his beloved wife, which caused him considerable disturbance. From 1564 he entrusted the government and the income of the State to his son Francesco, preserving for himself the ducal title. In the years immediately following, however, he continued to participate in the government of the Tuscan State, in collaboration with his son. In 1569, Pius V, to whom Cosimo had entrusted the heretic Carnesecchi, appointed him Grand Duke of Tuscany and the following year he solemnly crowned him in Rome. In recent years, he moved away from the court, residing in his country villas. He died in 1574