Saint Anthony, in the center of a broad landscape, is surrounded by three beautiful women who try to make him eat the apple of sin. Behind them, an old bawd represents trickery and incitation to evil. A monkey, considered an animal as lecherous as the young devils, pulls at the saint's clothes. In the middle ground are scenes from Jacopo de la Vorágnie's Golden Legend, including the diverse temptations Saint Anthony suffered at the hands of demons or beautiful nude women behind which the devil hides.

The landscape is typical of works by Patinir, with sharp crags in the middle ground and a high horizon. While only Patinir's signature appears on this work, Quentin Massys' participation in the depiction of the figures has been accepted since the mid sixteenth century. The model of the old woman is similar, in some ways, to his Old Woman Tearing at Her Hair (P03074).

This painting belonged to Felipe II, who gave it to El Escorial in 1574.