Saint Sebastian was a Roman soldier condemned to execution by arrows for defending his faith. Saint Irene freed him while he was still alive and cured his wounds. He was a very popular saint, perhaps because the power to stop plague epidemics was attributed to him.

Reni show the beginning of his martyrdom, when the Saint placed his life in God's hands. The strong contrast in light between the figure and the landscape in the background emphasize the drama of the scene. The choice of this instant also allows the artist to study the human body in tension but, despite the forced position, he manages to imbue it with his characteristic classicism.

There are two similar works, one in the Louvre and the other at the Dulwich Picture Gallery.

This painting appears in the 1746 inventory of the collection of Isabel de Farnesio (1692-1766) at the La Granja Palace in San Ildefonso, and in the 1794 inventory of the Palace of Aranjuez. In 1814 it was at Madrid's Royal Palace.