During his final years, the painter was overcome by a growing sense of paranoia. Certain that his enemies were hunting him down, he took to sleeping armed and in full armor.

Caravaggio died in 1610 at the age of 39. It is believed he was attempting to make the journey back to Rome, possibly seeking a pardon from the Pope. Human remains found in a church in Porto Ercole in 2010 are believed to almost certainly belong to the artist. Initial tests suggest he might have died of lead poisoning. Paints at the time contained high amounts of lead salts, and Caravaggio certainly indulged in the kind of violent behavior that is common with victims of lead poisoning. However, later research suggests that he died as the result of a wound sustained in a brawl in Naples, specifically from sepsis, and Vatican documents released in 2002 support the theory that the wealthy Tommasoni family had him killed.

The first Caravaggisti included Orazio Gentileschi and Giovanni Baglione. Baglione's Caravaggio phase was short-lived, and Caravaggio later accused him of plagiarism, leading to a long feud between the two artists. Caravaggio's influence can also been seen in the work of Peter Paul Rubens, Jusepe de Ribera, Gian Lorenzo Bernini, and Rembrandt.