No independent portraits of Cecco are known, making the identification impossible to verify, but "[a] sexual intimacy between David/model and Goliath/painter seems an inescapable conclusion, however, given that Caravaggio made David's sword appear to project upward, suggestively, between his legs and at an angle that echoes the diagonal linking of the protagonist's gaze to his victim".

The wild and riotous behaviour of the young Caravaggio essentially had destroyed his life as a mature adult, and he reflects with a familiar hermeticism on his own condition in a painting of a related religious subject.

[7] According to his biographer Bellori, the artwork had been commissioned to Caravaggio by Cardinal Scipione Borghese in 1606, a work that is possibly performed on a double easel, thus generating two twin masterpieces.

The biographical interest of the painting adds another layer of meaning to an already complex work, David and Goliath standing for Christ and Satan and the triumph of good over evil in orthodox Christian iconography of the period, and also as the cold-hearted beloved who "kills" and his lover according to contemporary literary conceit.

"David with the Head of Goliath [thus] demonstrates Caravaggio's gift for distilling his own experiences into an original sacred imagery that transcends the personal to become a searing statement of the human condition".