The shared works include the panels from a dismantled pair of cassoni, now divided among the Louvre, the National Gallery of Canada, the Musée Condé in Chantilly, and the Galleria Pallavicini in Rome.

The first ones (dating from 1475 onward) were attributed to an anonymous "Amico di Sandro" ("Friend of Botticelli"), a term introduced by Bernard Berenson in 1899, though by 30 years later his "lists" gave most of them to Lippi.

Soon after, probably in 1483–84, he was called to complete Masaccio's decoration of the Brancacci Chapel in the Santa Maria del Carmine di Firenze, that had been left unfinished when the artist died in 1428.

His self-portrait at age twenty-five is at the right hand portion of the central panel, Disputation with Simon Magus and Crucifixion of St. Peter (see detail at info box).

At about this time, Piero di Francesco del Pugliese asked him to paint the altarpiece with the Apparition of the Virgin to St. Bernard, which is now in the Badia Fiorentina, Florence.

These paintings have been considered as influenced by the political and religious crisis in Florence at the time: the theme of the fresco, the clash between Christianity and Paganism, was hotly debated during those years and in connection with Girolamo Savonarola.

Filippino depicted his characters in a landscape that recreated the ancient world in its finest details, showing the influence of the Grottesco style he had seen during his time in Rome.

In 1488, Lippi went to Rome, where Lorenzo de' Medici had advised Cardinal Oliviero Carafa to entrust him with the decoration of the family chapel in Santa Maria sopra Minerva.

Works of this period include: Apparition of Christ to the Virgin (c. 1493, now in Munich), Adoration of the Magi (1496, for the church of San Donato in Scopeto, now in the Uffizi), Sacrifice of Laocoön (end of the century, for the villa of Lorenzo de' Medici at Poggio a Caiano), St. John Baptist and Maddalena (Valori Chapel in San Procolo, Florence, inspired by Luca Signorelli's works).

The art critic Paul George Konody wrote of Lippi that "some of his qualities show him to be the most subtle psychologist of his time, the most modern in spirit of all the artists of the Renaissance".