Here he painted the portraits of the citizens hanged after the Battle of Anghiari on the facade of the Palazzo del Podestà, gaining the nickname of Andrea degli Impiccati.

In 1440–1441 he executed the fresco of the Crucifixion with Saints in the Hospital of Santa Maria Nuova, whose perspective-oriented construction and figures show the influence of Masaccio.

In 1447 Castagno worked in the refectory of the Benedictine nuns at Sant'Apollonia in Florence, painting, in the lower part, a fresco of the Last Supper,[2] accompanied above by other scenes portraying the Passion of Christ: the Crucifixion, Entombment, and Resurrection,[3] which are now damaged.

These include Pippo Spano, Farinata degli Uberti, Niccolò Acciaioli, Dante Alighieri, Petrarch, Giovanni Boccaccio, the Cumaean Sibyl, Esther and Tomyris.

Between January 1451 and September 1453 he completed the frescoes of Scenes of the Life of the Virgin left unfinished by Domenico Veneziano in the church of Sant'Egidio, Florence (now lost).

In 1456 he executed the fresco of the Equestrian Monument of Niccolò da Tolentino in the Duomo of Florence, paralleling the similar painting by Paolo Uccello portraying Sir John Hawkwood.