The present convent stands on a site occupied since the 12th century by a Vallombrosan monastery which later passed to the Silvestrines; they were driven out of San Marco in 1418, and in 1438 the convent was given to the Dominican Observants. In 1437 Cosimo il Vecchio de’ Medici decided to rebuild the entire complex, at the suggestion of Antonino Pierozzi the Vicar-General. The work was entrusted to Michelozzo, and the decoration of the walls was carried out between 1439 and 1444 by Giovanni of Fiesole, known as Fra Angelico, and his assistants, who included Benozzo Gozzoli. The church was consecrated in 1443 in the presence of Pope Eugenius IV. The 14th-century structure was modified by Michelozzo; further alterations were made in the later 16th century by Giambologna, and in 1678 by Pier Francesco Silvani. Inside, the aisle-less nave has a carved and gilded ceiling.

The side altars, designed by Giambologna in 1580, have 16th- and 17th-century altarpieces: the most interesting are the Madonna and Saints by Fra Bartolomeo (1509), and St. Thomas in prayer before the Crucifix, signed by Santi di Tito and dated 1593. In the Sacristy is the original tomb of St Antoninus, archbishop of Florence from 1446, with the figure of the Saint in bronze. His bones lay here for over a century, before they were translated to the church and placed beneath the altar in the Salviati Chapel dedicated to him, which was commissioned from Giambologna, and frescoed by Passignano with the Translation and recognition of the Saint’s remains (after 1589). The chapel is decorated in marble and bronze, and has paintings by Alessandro Allori, Giovanni Battista Naldini, and Poppi. The frescoes in the dome are by Bernardino Poccetti. He also frescoed the Chapel of the Blessed Sacrament, where there are canvases by Santi di Tito, Passignano, Jacopo da Empoli and Francesco Curradi. On the high altar is a Crucifix painted by Fra Angelico between 1425 and 1428. In San Marco are the tombs of Pico della Mirandola (1494) and the poet Agnolo Poliziano (1494).

Many of the great figures of 15th-century culture and spirituality lived and worked in the convent: Cosimo il Vecchio de’ Medici, who had his own cell here, where he loved to pray and meditate; Archbishop St Antoninus; the Blessed Fra Angelico, who painted the frecoes; and, from 1489, Fra Girolamo Savonarola, who in his sermons fulminated against the immorality of the age, and who was hanged and burnt in Piazza della Signoria (1498). Fra Angelico decorated the cells on the first floor, and other spaces in the convent, with frescoes charged with profound spiritual and ascetical meaning; he began with the lunettes above the doorways in the Cloister of St. Antoninus, which Michelozzo had built before 1440. The lunettes in the vaulting of the cloister were frescoed in the late 16th and early 17th century by Bernardino Poccetti and other artists with scenes of the Life and miracles of St Antoninus.

From this cloister we reach the rooms forming the Museum of San Marco. The Sala dell’Ospizio, where pilgrims were received, is now a gallery where many of Fra Angelico’s most important panel paintings have been gathered together. They include the Deposition painted for Palla Strozzi, the Pala di San Marco, commissioned by the Medici, and the Tabernacle of the Linaioli, made in 1433-1434 with the assistance of Lorenzo Ghiberti, who designed the frame. In the Chapter House, he painted a complex and allegorical Crucifixion, finished in 1442. In the other rooms of the Museum on the ground floor, such as the Lavabo and the two Refectories, are displayed works by the principal Florentine painters of the 15th and 16th century: Domenico Ghirlandaio, Alesso Baldovinetti, Giovanni Antonio Sogliani and Fra Bartolomeo.

The Great Refectory has a collection of works by the School of San Marco, in other words by the pupils of Fra Bartolomeo. In the Guest House there are numerous fragments of stone carvings, rescued from the ruins when the Jewish quarter and the old market in Florence were demolished in the mid-19th century.

The Museum also includes the former Library on the first floor, built by Michelozzo for Cosimo de’ Medici, where a considerable number of illuminated choir books are displayed. The present Convent Library specialises in theology and philosophy.