The series was produced by Italian companies Lux Vide and Rai Fiction, in collaboration with Spotnitz's Big Light Productions.

His son Cosimo succeeds him as head of the family bank, the richest in Europe at the time, and fights to preserve his power in Florence.

Meanwhile, the political situation in the city is troubled by plots against the Medici family's power, and their vision of the future of Florence—which will then lead to the Renaissance—is in danger.

Cosimo's dream is to complete the Duomo of Florence, but no architect seems to have a feasible solution due to the shape of the base created for the cathedral.

Meanwhile, the mystery surrounding the death of Giovanni thickens and Rinaldo Albizzi, Cosimo's main opponent in the Signoria, tries to block the construction and to incite the people to rise up against the Medicis.

The power of the Medici has consolidated over time, but an assassination attempt on Piero brings to light his mismanagement of the family bank.

His brother Giuliano and his dear friend Sandro Botticelli both meet and fall in love with Simonetta, although in different ways.

This argument will eventually lead to a conspiracy against Lorenzo in an attempt to put an end to his power and his dream of a peaceful and culturally alive Florence.

With his brother's death and the counsel of his new ruthless advisor Bruno Bernardi, Lorenzo has grown into a cruel determined man and vows revenge.

[17] During an interview at the Roma Fest panel in 2015, Spotnitz stated, "the season will be more thriller than historical saga... we begin the show with a 'what if' because we don't know how Giovanni de' Medici died.

For example, the Medici Palazzo was built in 1440s–1480s and the Benozzo Gozzoli frescoes of Magi Chapel shown in the Cosimo study were executed in 1459–61.

The Lorenzo rooms are decorated with the Giulio Romano fresco "Mars and Venus" which was painted in the 1520s in Palazzo Te in Mantova.

Two audio tracks were broadcast: Rai TV gave satellite and terrestrial viewers the option to watch the series in Italian or English.

On 16 October 2018, a novelisation of the events told in the second season titled I Medici – Lorenzo il Magnifico was published in Italy by Michele Gazo.