The son of Fra Filippo Lippi (Lippi, Fra Filippo) and his wife, Lucrezia Buti, he was a follower of his father and of Botticelli. After Fra Filippo Lippi's death, Filippino entered the workshop of Botticelli. By 1473 he had finished his apprenticeship. The style of Filippino's earliest works stems from that of Botticelli, but Filippino's use of line is less sensitive and subtle than Botticelli's. In a group of paintings executed about 1480–85 he developed a harder and more individual style. Among the most notable works of this period is the “Journey of Tobias” in the Galleria Sabauda, Turin, Italy. He was employed, along with Botticelli, Perugino, and Ghirlandaio, on the frescoed decoration of Lorenzo de' Medici's villa at Spedaletto and at the end of 1482 was commissioned to complete work left unfinished by Perugino in the Palazzo della Signoria in Florence. No trace of either work survives. Soon after (probably 1483–84) he was entrusted with the completion of the frescoes in the Brancacci Chapel in the Carmine, which had been left unfinished on Masaccio's death in 1428.

His most popular picture, the beautiful altarpiece of “The Vision of St. Bernard” (Badia, Florence), has been variously assigned to the years 1480 and 1486. In Rome Filippino decorated the Carafa Chapel in Sta. Maria sopra Minerva. Nothing in Filippino's earlier works prepares for the vein of inspiration that he struck in the Carafa Chapel, which became one of his most influential works.

After his return from Rome, Filippino executed a fresco of the “Death of Laocoön” for the villa of Lorenzo de' Medici at Poggio a Caiano, in which some of the decorative devices used in the Carafa Chapel are again employed, and resumed work in the Strozzi Chapel (completed 1502), the frescoes of which anticipate Tuscan Mannerism of the 16th century.