Among Perugino's frescoes in the Chapel, the Christ Giving the Keys to St. Peter is stylistically the most instructive. This scene is a reference to Matthew 16 in which the "keys of the kingdom of heaven" are given to St.Peter.[1] These keys represent the power to forgive and to share the word of God thereby giving them the power to allow others into heaven. The main figures are organized in a frieze in two tightly compressed rows close to the surface of the picture and well below the horizon. The principal group, showing Christ handing the silver and gold keys to the kneeling St. Peter, is surrounded by the other Apostles, including Judas (fifth figure to the left of Christ), all with halos, together with portraits of contemporaries, including one said to be a self-portrait (fifth from the right edge). The flat, open square is divided by coloured stones into large foreshortened rectangles, although they are not used in defining the spatial organization. Nor is the relationship between the figures and the felicitous invention of the porticoed Temple of Solomon that dominates the picture effectively resolved. The triumphal arches at the extremities appear as superfluous antiquarian references, suitable for a Roman audience. Scattered in the middle distance are two secondary scenes from the life of Christ, including the Tribute Money on the left and the Stoning of Christ on the right.

The style of the figures is inspired by Andrea del Verrocchio. The active drapery, with its massive complexity, and the figures, particularly several apostles, including St. John the Evangelist, with beautiful features, long flowing hair, elegant demeanour, and refinement recall St Thomas from Verrocchio's bronze group in Orsanmichele. The poses of the actors fall into a small number of basic attitudes that are consistently repeated, usually in reverse from one side to the other, signifying the use of the same cartoon. They are graceful and elegant figures who tend to stand firmly on the earth. Their heads are smallish in proportion to the rest of their bodies, and their features are delicately distilled with considerable attention to minor detail.

The octagonal temple of Jerusalem and its porches that dominates the central axis must have had behind it a project created by an architect, but Perugino's treatment is like the rendering of a wooden model, painted with exactitude. The building with its arches serves as a backdrop in front of which the action unfolds. Perugino has made a significant contribution in rendering the landscape. The sense of an infinite world that stretches across the horizon is stronger than in almost any other work of his contemporaries, and the feathery trees against the cloud-filled sky with the bluish-gray hills in the distance represent a solution that later painters would find instructive, especially Raphael.

The fresco was believed to be a good omen in papal conclaves: superstition held that the cardinal who (as selected by lot) was housed in the cell beneath the fresco was likely to be elected. Contemporary records indicate at least three popes were housed beneath the fresco during the conclaves that elected them: Pope Clement VII, Pope Julius II, and Pope Paul III.