He commissioned the execution of the frescoes from the most famed artist of the city, Domenico Ghirlandaio. The date of the contract is that signed next to the portraits of Sassetti and his wife (December 25 1480), although the work was not carried out until between 1483 and 1486. The central altarpiece, depicting the Adoration of the Shepherds, is dated 1485.
Ghirlandaio portrayed numerous figures of contemporary Florentine society in the scenes. All the work shows the importance of the influence on Ghirlandaio of Flemish school, in particular the Portinari Triptych by Hugo van der Goes, taken by him to Florence in 1483 and now in the Uffizi.
The Chapel was restored in 2004.
The fresco cycle covers three walls framed by fictive architectural elements. The altarpiece is also framed by a painted marble decoration. The two side walls house the tombs of Francesco Sassetti and his wife Nora Corsi, under a gilded arch, a creation of Giuliano da Sangallo. At the side of the altar are kneeling portraits of the two patrons, Nora Corsi on the left and Sassetti on the right: they direct their prayers towards the central altarpiece of the Adoration of the Shepherds, also by Ghirlandaio.
Ghirlandaio's frescoes can also be seen in the upper transept wall, outside the chapel. This area was plastered in the 18th century, the paintings being rediscovered only in 1895, which accounts for their poorer state of conservation. The work outside the Sassetti chapel is attributed to the three Ghirlandaio brothers (Domenico, David and Benedetto) and assistants. Its perspective was devised to offer a perfect view from below.
The first scene painted above the chapel is the Tiburtine Sibyl Announces Jesus' Coming to Augustus. The Sibyl is probably a portrait of Sassetti's daughter, Sibilla. On the pilaster dividing the Sassetti Chapel from the subsequent one is a painted grisaille statue of David. In the vault of the chapel are the four Sibyls, surrounded by flaming aureoles and holding out banderoles describing their prophetic role as assigned them by Virgil:
Only the faces of the Sibyls are attributed to Ghirlandaio; the bodies were probably executed by his workshop.
- Hec teste Virgil Magnus, in ultima autem etate;
- Invisibile verbum palapabitur germinabit.
The fresco cycle extends over three walls of the chapels, and includes six scenes:
Ghirlandaio had possibly never seen the Stories of St. Francis in the Basilica di San Francesco in Assisi, but he must certainly have known those in the Bardi Chapel of Santa Croce in Florence, painted by Giotto in the early 14th century.
A drawing, now in Berlin, shows that initially Ghirlandaio had intended a more traditional iconography following that of the frescoes in Santa Croce and without the portraits. Later he modified it, dividing the pictorial space into three planes: the steps, the church and the background. On the right, in the foreground, are Sassetti's brother-in-law, the Gonfaloniere di Giustizia Antonio Pucci; Sassetti's employer, Lorenzo de' Medici; Francesco Sassetti himself and his son Federico. Lorenzo raises his hand to greet Agnolo Poliziano, the tutor of his sons who are featured ascending the stairs. They are Giuliano, Piero and Giovanni, the future Pope Leo X, followed by other members of the Humanist Academy, Luigi Pulci and Matteo Franco. Sassetti is pointing out his older sons on the other side of the stairs: Galeazzo, Teodoro and Cosimo.
This painting, which is considered one of Ghirlandaio's masterpieces, provides the most reliable portraits of these various 15th century people, as, unlike the work of Botticelli, who also painted members of the Medici household, they are neither stylised, nor do they appear to be idealised.
The three people on the right, a father with his son and nephew, are probably connected to the Sassetti family. On the right the tutor Poliziano is again portrayed alongside Bartolomeo Fonzio.
The resurrected boy is in the middle of the composition, sitting with his hands together on a bed covered with Eastern-style drapes. St. Francis, appearing as an apparition, blesses him from the sky, while, on either side, a group of people attend the scene. Among the people portrayed are numerous figures from contemporary Florence. The five women on the left are probably Sassetti's daughters, their husbands or fiancées being visible on the right in the foreground. The last man in the first left row is Ghirlandaio himself. Also notable is the presence of a Moorish female servant. Other figures portrayed on the right include Maso degli Albizzi, Angelo Acciaioli, Palla Strozzi and Neri di Gino Capponi. The last two people on the right are probably Poliziano and Fonzio.
The scene is also important as it shows in detail the appearance of the Santa Trinita's piazza in the 15th century, with the old Romanesque façade of the church, Palazzo Spini Feroni still with the appearance of a fortress and an undecorated Ponte Santa Trinita. The three figures behind the bier are attributed to assistants.
The Adoration of the Shepherds was painted in 1485. It is recognized as one of Ghirlandaio's masterpieces, as well as one of the Florentine painting school. The work shows clear influences of the Flemish school, the artist having studied Hugo van der Goes' Portinari Altarpiece, which had been taken to Florence in 1483 by the Portinari family for the church of Sant'Egidio. Ghirlandaio's inspiration from that work is shown by positioning and realist handling of the three shepherds on the right, one of which is the artist's self-portrait. The frame has the inscription "Ipsum quem genuit adoravit Maria" ("The one giving adoration to Mary"), probably a reference to Ghirlandaio himself.
Also influenced by Flemish painting is the attention to detail: every object has a precise symbolic role; and the well-rendered airy perspective, with the landscape fading towards a detailed representation of a hill and a town. The farthest city, on the right, is a symbolic Jerusalem with the domed edifice; in front of it is a dead tree, a reference to its conquest. The left city represents Rome, with the two sepulchres of the "prophetic" emperors, Augustus and Hadrian (who, at the time, was thought to be buried under the Torre delle Milizie). In the city, however, a church resembling Santa Maria del Fiore can be seen, a hint of the role of Florence as a new Rome.
The altarpiece is flanked by the two kneeling portraits of the donors.
The scene is set on a flowering lawn, with Mary to the left foreground, kneeling in front of the Child. The manger, before which the Child lies, is an ancient Roman sarcophagus with the inscription "Ense cadens soly mo Pompei Fulvi[us] augur Numen aitquae me conteg[it] urna dabit", an allusion of the coming of Christ through the prophecy of Fulvius, killed by Pompey the Great during the Roman conquest of Jerusalem. The prophecy said that from the sarcophagus housing his remains a God will rise, a reference to the victory of Christianism over Paganism.
Next to Mary is St. Joseph looking upwards as, in the background, an angel is announcing to the shepherds the coming of Christ, while on the left, the long procession of the Magi is passing under a triumphal arch. The latter has the inscription: "Gn[eo] Pompeo Magno Hircanus Pont[ifex] P[osuit]" ("The priest Hircanus erected [this arch] in honor of Gnaius Pompey the Great"). On the left, the two nearest Magi are staring at a light visible from above the hut's roof, coming perhaps from the star. Behind the sarcophagus are an ox and a donkey, symbols of the Jews and the Gentiles.