He was employed for many years in the building works (Fabbrica di Santa Maria del Fiore) of Florence Cathedral[3] as a "quarryman, stonemason, master builder, and designer".

[2] Nanni received the training typical of a Florentine artisan, being descended from stonemasons who were active in the Opera di Santa Maria del Fiore.

He joined the stonemasons' and woodworkers' guild (arte dei maestri di pietra e legname) in 1405, and is first noticed in the cathedral documents (1406–1408) during the second phase or "campaign" of the decoration of the Porta della Mandorla (Almond Gate).

He sculpted the archivolt of the door in which a Christ in Pity (Cristo in pietà) or Man of Sorrows[4] is carved on the keystone at the top of the frieze and framed by a pentagon (1407–1409).

Giovanni d'Ambrogio, whose work, according to Kreytenberg, "provided a decisive impetus for the emergence of Renaissance sculpture", has been described by Manfred Wundram as the "true mentor of Donatello, and even more so of Nanni di Banco".

His name appeared on the cathedral payroll in 1395 along with those of Niccolò Lamberti, Lorenzo di Filippo, and Giovanni d'Ambrogio, accomplished masters active in the first campaign of work on the Porta della Mandorla.

[2] After the completion of the cathedral's northwest tribune in 1407–1408, several stonemasons, including Antonio di Banco, were commissioned by the Operai to adorn the spurs of the buttresses with twelve life-sized statues of Old Testament prophets.

Donatello's marble David remained at the Opera del Duomo until July 1416,[14] when it was given to the Priors of the Arts (Priori delle arti) and moved to the Palazzo della Signoria.

The whereabouts of Nanni's Isaiah remained unknown until Lányi showed in 1936 that it must have been the statue in the nave of the church on the right side of the entrance, moved there after the facade was demolished in 1587.

During this period Nanni was completing the Quattro Santi Coronati, working assiduously on the Assumption of the Virgin and beginning to carve the Saint Eligius in Orsanmichele for the blacksmiths' guild.

[2] To maintain sole authority over their projects, the Operai as a matter of course organized them as joint enterprises among the painters, sculptors, and architects involved, denying any single participant a free hand and encouraging them to collaborate.

This approach caused the artists to compete with each another and to seek recognition for the excellence of their work, leading to greater efficiency in completing the programs and thereby keeping costs lower.

The project to create the set of the four evangelists is documented from purchase of the marble (1405–1407) until the relocation of the statues in the Museo dell'Opera del Duomo after World War II.

[2] One of the earliest examples of the development of contrapposto in the Quattrocento is Nanni's Saint Philip, a standing, draped figure, located on the north side of Orsanmichele.

[22] Demonstrating his familiarity with antique prototypes of formal sculpture, Nanni depicted the four saints, sculptors who were martyred in the 4th century, as if they were Roman philosophers or senators.

Nanni acted, for example, as Donatello's guarantor to the Opera del Duomo for payments made in advance for work on the Prophets series in the campanile.