San Samuele bears the distinction of being one of only a handful of Roman Catholic churches dedicated to an Old Testament figure.

The walls and vaults of this apse have been restored starting in 1999, and are one of the few surviving fresco cycles of the early Venetian Renaissance.

The cycle depicts eight Sibyls, Greek and Roman female seers who were believed to have predicted events in the life of Christ such as the Annunciation, the Crucifixion and the Resurrection.

The ceiling's quadripartite vault features Saints Jerome, Augustine, Ambrose and Gregory, the four fathers of the Western church, set in roundels and surrounded by inscriptions, decorative foliage, and putti bearing the instruments of the Passion.

Above the high altar, the frescoes occupying the spaces between the ribs of the cupola feature Christ and the four Evangelists Matthew, Mark, Luke and John.