The prototype for this picture is one of the series of four paintings depicting episodes from the story of Hercules by Reni in the Louvre. The series was executed for Frederico Gonzaga, Duke of Mantua, between 1617 and 1621. Sold to King Charles I of England in 1627, they subsequently passed into the collection of King Louis XIV of France. There is a study for the figure of Deianeira in the Uffizi, Florence.
Philostratus the Younger relates in his Eikones that Hercules and his wife, Deianeira, the daughter of the river-god Oeneus, came to a river where the Centaur Nessus was the ferryman. Nessus, whilst carrying Deianeira across the river, attempted to ravish her, and was shot by Hercules with an arrow. Hercules' arrrows were poisoned with the gall of the Lernaean Hydra (the subject of one of the twelve tasks), and Nessus, knowing that his blood was now also poisoned, told Deianeira to keep it as a love potion. The unwitting woman did so, and when she later used it on one of Hercules' robes, caused his death and apotheosis.