Ghirlandaio's full name is given as Domenico di Tommaso di Currado di Doffo Bigordi. The occupation of his father Tommaso Bigordi and his uncle Antonio in 1451 was given as "'setaiuolo a minuto,' that is, dealers of silks and related objects in small quantities." He was the eldest of six children born to Tommaso Bigordi by his first wife Mona Antonia; of these, only Domenico and his brothers and collaborators Davide and Benedetto survived childhood. Tommaso had two more children by his second wife, also named Antonia, whom he married in 1464. Domenico's half - sister Alessandra (b. 1475) married the painter Bastiano Mainardi in 1494.

Domenico was at first apprenticed to a jeweller or a goldsmith, most likely his own father. The nickname "Il Ghirlandaio" (garland - maker) came to Domenico from his father, a goldsmith who was famed for creating the metallic garland - like necklaces worn by Florentine women. In his father's shop, Domenico is said to have made portraits of the passers - by, and he was eventually apprenticed to Alessio Baldovinetti to study painting and mosaic. According to Gunter Passavent he was apprenticed in Florence to Andrea del Verrocchio.

In 1480, Ghirlandaio painted the Saint Jerome in His Study and other frescoes in the Church of Ognissanti, Florence, and a life - sized Last Supper in its refectory. From 1481 to 1485, he was employed on frescoes in the Sala dell' Orologio of the Palazzo Vecchio. He also painted the Apotheosis of St. Zenobius, an over - life - sized work with an elaborate architectural framework, figures of Roman heroes, and other secular details, striking in its perspective and structural / compositional skill.

In 1483, Ghirlandaio was summoned to Rome by Pope Sixtus IV to paint a wall fresco in the Sistine Chapel, Vocation of the Apostles; also attributed to him is the Crossing of the Red Sea, although more likely executed by Cosimo Rosselli or Biagio d'Antonio. Although he is known to have created other works in Rome, they have been for centuries considered lost to history. He also produced frescoes, dated before 1485, for Cappella di Santa Fina, in the Tuscan Collegiata di San Gimignano which came under the rule of nearby Siena at the beginning of the 1350s. His future brother - in - law, Sebastiano Mainardi, assisted him with these commissions in Rome and in San Gimignano.

Back in Florence in 1485, Ghirlandaio painted fresco cycles in the Sassetti Chapel of Santa Trinita for the donor and banker Francesco Sassetti, the powerful manager of the branch of the Medici bank in Genoa, a position subsequently filled by Giovanni Tornabuoni, Ghirlandaio's future patron. In the chapel, Ghirlandaio painted six scenes from the life of Saint Francis, including Saint Francis obtaining from Pope Honorius the Approval of the Rules of His Order, Death and Obsequies and Resuscitation, by the interposition of the beatified saint, a child of the Spini family, who died as a result of a fall from a window. The first work depicts a portrait of Lorenzo de' Medici, and the third, the painter's own likeness, which he also included in one of his pictures in the Santa Maria Novella as well as in the Adoration of the Magi in the Ospedale degli Innocenti orphanage. The altarpiece from the Sassetti chapel, the Adoration of the Shepherds, is now in the Florentine Academy.

Immediately after this commission, Ghirlandaio was asked to renew the frescoes in the choir of Santa Maria Novella, which formed the chapel of the Ricci family, but the Tornabuoni and Tornaquinci families, which were much more prominent than the Ricci, undertook the cost of the restoration, with conditions — the question of preserving the arms of the Ricci gave rise to what some historians described as amusing litigation. The Tornabuoni Chapel frescoes, by Ghirlandaio and many assistants, were painted in four courses along the three walls, the main subjects being the lives of the Madonna and St. John the Baptist. These works are particularly interesting in that they include many historical portraits, a genre in which Ghirlandaio was preeminently skilled.

In this cycle, there are no fewer than twenty-one portraits of the Tornabuoni and Tornaquinci families – in the Angel appearing to Zacharias, portraits of Politian, Marsilio Ficino and others; in the Salutation of Anna and Elizabeth, the beautiful Giovanna Tornabuoni (identified (incorrectly) by Giorgio Vasari as Ginevra de Benci); in the Expulsion of Joachim from the Temple, Sebastiano Mainardi and Alessio Baldovinetti (some art historians have surmised that the latter figure may be the likeness of Ghirlandaio's father). The Tornabuoni Chapel was completed in 1490; the altarpiece was probably executed with the assistance of Domenico's brothers, Davide and Benedetto; the painted window was from Domenico's own design.

Other distinguished works from Ghirlandaio's hand are an altarpiece in tempera of the Virgin Adored by Saints Zenobius, Justus and Others, painted for the church of Saint Justus, and considered a remarkable masterpiece — in modern times it has been in the Uffizi gallery. Christ in Glory with Romuald and Other Saints, in the Badia of Volterra; and the Visitation (Louvre) which bears the last ascertained date (1491) of all his works. Ghirlandaio did not often attempt the nude — one of his pictures including nudes, Vulcan and His Assistants Forging Thunderbolts, was painted for Lorenzo II de' Medici, but, as in the case of several others specified by Giorgio Vasari, no longer exists. The mosaics that he produced date before 1491 — one, of special note, is the Annunciation, on a portal of the cathedral of Florence.

Ghirlandaio's compositional schema were simultaneously grand and decorous, in keeping with 15th century's restrained and classicizing experimentation. His chiaroscuro, in the sense of realistic shading and three - dimensionalism, was reasonably advanced, as were his perspectives, which he designed on a very elaborate scale by eye alone, without the use of sophisticated mathematics. His color is more open to criticism, but such evaluation applies less to the frescoes than the tempera paintings, which are sometimes too broadly and crudely bright. His frescoes were executed entirely in buon fresco which, in Italian art terminology, refers to abstention from additions in tempera.

A certain hardness of outline may attest to his early training in metal work. Vasari states that Ghirlandaio was the first to abandon, in great part, the use of gilding in his pictures, representing by genuine painting any objects supposed to be gilded; yet this claim is not applicable to his entire oeuvre, since the landscape highlights in, as an example, the Adoration of the Shepherds located, in modern age, at the Florence Academy, were rendered in gold leaf. Those of his drawings and sketches which can be observed and studied at the Uffizi gallery, are considered particularly remarkable for their naturalistic vigor of outline.

One of the great legacies of Ghirlandaio is that he is commonly credited with having given some early art education to Michelangelo, who cannot, however, have remained with him long. Francesco Granacci is another among his best known pupils.

Ghirlandaio died of "pestilential fever" and was buried in Santa Maria Novella. The day and month of his birth remain undocumented, but since he died in early January of his forty - fifth year, he most likely did not reach that birthday. He had been twice married and left six children. One of his three sons, Ridolfo Ghirlandaio, also became a noted painter. Although he had a long line of descendants, the family died out in the 17th century, when its last members entered monasteries.