The theme, popular among humanists of the period, derives from Apollodorus, Bibliotheke2:5-11, Diodorus Siculus, Bibliotheca Historica 4 and Ovid's Methamorphosis IX, 182-183, and was introduced in Northern Europe through Italian graphic. It gave a unique opportunity to study human body and muscles strained in the struggle. The subject was developed and distributed in printing by such artists as Antonio Pollaiuolo, whose small picture created for Lorenzo il Magnifico preserved in Uffizi (oil tempera on panel, 16 × 9 cm (6.3 × 3.5 in), inventory number 1890, 1478) was converted into print by Cristofano Robetta, and Raphael, whose drawing was recorded by a chiaroscuro print by Ugo da Carpi (before 1520) and by an engraving by Marcantonio Raimondi. It seems that the artist known both compositions and took the pose from Pollaiuolo and the concept of the background from Raphael.
In this work Grien is not paying great attention to details, the line is superior. The figures, inseparable in their passionate wrap, are contrasted in colour to emphasize the defeat and death of Antaeus.The painting is filled with some level of homo-eroticism and according to Gert von der Osten can be interpreted as victory of virtue over carnal desire. It was included in a list of pictures shown in the temporary exhibition of homoerotic art - Ars Homo Erotica between 11 June 2010 and 5 September 2010 in Warsaw's museum as an allusion ''to some man-man physical contact in dynamic, sensuous or sadomasochistic mise-en-scene" (Paweł Leszkowicz).
Inscription in upper part of the pillar DIVO HERCULI (Divine Hercules) is in some way ironic. The artist is opposing destructive, ruthless and raw force represented by a rock to creative inventiveness and intelligence represented by partially destroyed architecture, forces of nature to the human activity, previous epoch to the new one of the Renaissance. It was dated by the artist on a stone block on bottom left - 1530.
In the context of Christian humanism interpretation and due to similar dimensions the work can be placed among the cycle reconstructed in 1959 and depicting virtues in antique entourage - Pyramus and Thisbe, Death of Marcus Curtius, Mucius Scaevola before Porsenna and Lucretia. According to the authors of Malarstwo niemieckie do 1600 roku (German painting till 1600), Bożena Steinborn and Antoni Ziemba, the reduced, stage-like space can indicate the inspiration from theater.
Grien painted the battle of Hercules against the giant Antaeus several times, another version is in the Museumslandschaft Hessen Kassel (oil on limewood, 1531, 153.5 × 65.3 cm (60.4 × 25.7 in), inventory number GK 7, inscribed and signed DIVO HERCVLI/1531/HBG), while a drawing preserved in the Cabinet des estampes et des dessins in Strasbourg (watercolor and ink on paper, ca. 1530, 27.8 × 15.7 cm (10.9 × 6.2 in), inventory number CE XXXXVI.46 ; 77.R.2009.0110, not signed). Strasbourg coposition is in some way a transition between earlier Warsaw painting and later Kassel version. Pose and presence of a rock makes it more close to Warsaw version while other details are similar with Kassel picture (background, frontality, position of lion's skin and more studied muscles). It seems that in Warsaw's painting the artist focused more on background to convey additonal meaning.
Between 1807 to 1852, the painting was in the possession of Society of Patriotic Friends of the Arts in Prague, to be acquired in 1928 by the Silesian Museum of Fine Arts in Wrocław from B. Kolowrat Krakowský-Liebsteinsky collection in Rychnov Castle (Drey Auction House in Munich). It was transferred to the National Museum from the Nazi German Repository in Kamenz (Kamieniec Ząbkowicki, Polish Regained Territories) in 1946.