The saint is dressed in furs, has long curly hair and is smiling in an enigmatic manner reminiscent of Leonardo's famous Mona Lisa.

According to Frank Zöllner, Leonardo's use of sfumato "conveys the religious content of the picture", with the "gentle shadows [imbuing] the subject's skin tones with a very soft, delicate appearance, almost androgynous in its effect".

[2] Kenneth Clark claimed that for Leonardo, Saint John represented "the eternal question mark, the enigma of creation", and noted the sense of "uneasiness" that the painting imbues.

[3] Barolsky adds that: "Describing Saint John emerging from the darkness in almost shockingly immediate relation to the beholder, Leonardo magnifies the very ambiguity between spirit and flesh.

In 1625, King Charles I of England received the painting from Louis XIII of France in return for a Titian – the Holy Family – and Hans Holbein's Portrait of Erasmus.