1610. The Renaissance painter, Caravaggio, is wanted for murder and has been on the run for four years. He is dying and being cared for by his young apprentice, John Jerusaleme, a deaf mute who Caravaggio took in as a boy. Caravaggio narrates episodes of his life, and muses on his approaching death.

As a young artist, Caravaggio offers sexual favours, as well as portraits. "I'm an art object and I'm very expensive," he tells one client. A cardinal, who dreams of paintings he could love, shows interest in his work and becomes his patron, teaching him to read and understand rudimentary philosophy.

He meets Lena and Ranuccio, a young couple, who become his models and lovers. Jealousy erupts among the three and Caravaggio is wounded by Ranuccio in a fight. It is clear when they attend an unveiling of one of Caravaggio's commissioned works at a palace, and steal jewellery from the rich, that the artist and his friends will never be accepted. When Lena gets pregnant, and is murdered, Ranuccio is blamed and put in jail. Later, Caravaggio seeks to free him and frame a young aristocrat, Scipone Borghese, for Ranuccio's release. When Ranuccio confesses that he killed Lena for his love for Caravaggio, the artist murders the young man.

The film closes with the funeral of Caravaggio and the artist as a young boy seeing an enactment of the Passion, played by locals, and Christ and the figure of the artist are one in his mind.