The Sant'Onofrio Altarpiece is a painting by the Italian Renaissance painter Luca Signorelli, housed in the Museo dell'Opera del Duomo in the Cathedral of Perugia, Italy.

It was painted for the church in 1484, commissioned by bishop Jacopo Vagnucci, a native of Cortona, Signorelli's birthplace.

The scene portrayed is a Holy Conversation, with a high throne where the Virgin and Child sit, placed over a Classical-style pedestal and crowned by a small engraved arch featuring a festoon with vegetables.

On the marble step below, Signorelli portrayed a sitting angel playing a lute, perhaps a homage to elements typical of the contemporary Venetian school (such as the San Cassiano Altarpiece by Antonello da Messina).

The angel resembles one painted by Signorelli in the Basilica della Santa Casa, at Loreto, a few years earlier.