The upper register of the painting shows the Transfiguration itself (on Mount Tabor, according to tradition), with the transfigured Christ floating in front of illuminated clouds, between the prophets Moses, on the right, and Elijah, on the left with whom he is conversing.

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In the lower register, Raphael depicts the Apostles attempting to free the possessed boy of his demonic possession. They are unable to cure the sick child until the arrival of the recently transfigured Christ, who performs a miracle. The youth is no longer prostrate from his seizure but is standing on his feet, and his mouth is open, which signals the departure of the demonic spirit. As his last work before this death, Raphael, joins the two scenes together as his final testament to the healing power of the transfigured Christ.

According to Goethe: "The two are one: below suffering, need, above, effective power, succour. Each bearing on the other, both interacting with one another."

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Raphael's Transfiguration can be considered a prefiguration of both Mannerism, as evidenced by the stylised, contorted poses of the figures at the bottom of the picture; and of Baroque painting, as evidenced by the dramatic tension imbued within those figures, and the strong use of chiaroscuro throughout.