The painting portrays the 333 BC Battle of Issus, in which Alexander the Great secured a decisive victory over Darius III of Persia and gained crucial leverage in his campaign against the Persian Empire.

Duke William IV of Bavaria commissioned The Battle of Alexander at Issus in 1528 as part of a set of historical pieces that was to hang in his Munich residence.

Modern commentators suggest that the painting, through its abundant use of anachronism, was intended to liken Alexander's heroic victory at Issus to the contemporary European conflict with the Ottoman Empire.

When he was satisfied that the left wing was crippled and no longer a threat, Alexander remedied the situation by moving the Companions to assault the Persian centre in the flank.

As evidenced by such paintings as Saint George in the Forest (1510) and Allegory (1531), much of Altdorfer's work is characterised by an attachment to sprawling landscapes that dwarf the figures within them;[30] The Battle of Alexander at Issus epitomises this facet of his style.

With reference to Saint George in the Forest in particular, art historian Mark W. Roskill comments that "The accessory material of landscape [in Altdorfer's work] is played with and ornamentally elaborated so that it reverberates with the sense of a sequestered and inhospitable environment".

This meaning is not uniform throughout Altdorfer's corpus – for example, the visage of the setting sun connotes loss and tragedy in Agony in the Garden, but serves as "the emblem of power and glory" in The Battle of Alexander at Issus.

[35] Larry Silver of The Art Bulletin explains that The Battle of Alexander at Issus is both similar to and in direct contrast with Altdorfer's previous work: "Instead of the peaceful landscape of retreat for Christian events or holy figures, this panel offers just the opposite: a battleground for one of ancient history's principal epoch-making encounters ...

Yet despite its global or cosmic dimensions, the Battle of Issus still looks like Altdorfer's earlier, contemplative liminal landscapes of retreat, complete with craggy peaks, bodies of water, and distant castles.

"[36] Although the Battle of Alexander is atypical of Altdorfer in its size and in that it depicts war, his Triumphal Procession – a 1512–16 illuminated manuscript commissioned by Maximilian I of the Holy Roman Empire – has been described as a conceptual antecedent.

[39] Elements of The Battle of Alexander at Issus – particularly the sky – have been compared to Grünewald's Heavenly Host above the Virgin and Child, which forms part of his masterpiece, the Isenheim Altarpiece.

He declined; the council annals reported his reasoning as such: "He much desires to execute a special work in Bavaria for my Serene Highness and gracious Lord, Duke [William].

"[44] William probably wanted the painting for his newly built summer Lusthaus ("pleasure house") in the grounds of his palace in Munich, approximately 60 miles (97 km) south of Regensburg.

One of the few named women painters who might have worked in Ancient Greece,[50][51] she was reputed to have produced a painting of the battle of Issus which hung in the Temple of Peace during the time of Vespasian.

[57] The scene is approached from an impossible viewpoint – at first only feet from the fray, the perspective gradually ascends to encompass the seas and continents in the background and eventually the curvature of the Earth itself.

The two armies are distinguished by their dress, anachronistic though it is: whereas Alexander's men clad themselves and their horses in full suits of heavy armour, many of Darius' wear turbans and ride naked mounts.

[47] The tract of soldiers continues down the gently sloped battlefield to the campsite and cityscape by the water, gravitating toward the mountainous rise at the scene's centre.

[57] The rain-heavy clouds swirling ominously around each celestial entity are separated by a gulf of calmness, intensifying the contrast and infusing the heavens with an unearthly glow.

[44][59][64] In 1529 – the year of the painting's commissioning – the Ottoman forces under Suleiman the Magnificent laid siege to the Austrian city of Vienna,[64] then also the capital of the Holy Roman Empire and called 'the golden apple' by the Sultans.

Although far inferior in number, the Austrian, German, Czech, and Spanish soldiers marshalled to defend Vienna were able to force the enemy into a retreat and stall the Ottoman advance on central Europe.

In such a system there can be no event as such: anticipation and arrival are together sucked into the black hole of sacred history, which is not temporalized because its time is essentially undifferentiated ..."[65] Featured alongside the anachronism in The Battle of Alexander at Issus is a genuine lack of historicity.

Altdorfer demonstrates minimal hesitance in neglecting the painting's historical integrity for the sake of its heroic style, in spite of the pains he took to research the battle.

Furthermore, the errors in Schedel's maps of the Mediterranean and Northern Africa are also present in The Battle of Alexander at Issus: the island of Cyprus is noticeably oversized, and both the mountain rise in the painting's centre and the range adjacent to the Nile do not exist.

[61] Since the Chronicle describes Alexander's victory over the Persians in terms of its proximity to Tarsus and omits mention of Issus, it is likely that the cityscape by the sea is intended to be the former city rather than the latter.

[61] Another source may have been the writings of Quintus Curtius Rufus, a 1st-century Roman historian who presents inflated figures for the number of killed and taken prisoner and the sizes of the armies.

When the Prussians captured the Château de Saint-Cloud in 1814 as part of the War of the Sixth Coalition, they supposedly found the painting hanging in Napoleon's bathroom.

The Renaissance induced a new kind of social individualism which Altdorfer expressed through the heroic emphasis on Alexander and Darius, and which is reflected in the specifics of the painting's commission and by the subjects of its companion pieces.

Kenneth Clark writes of Altdorfer and contemporaries Grünewald and Bosch, "They are what we now call 'expressionist' artists, a term which is not as worthless as it sounds, because, in fact, the symbols of expressionism are remarkably consistent, and we find in the work of these early 16th-century landscape painters not only the same spirit but the same shapes and iconographical motives which recur in the work of such recent expressionists as van Gogh, Max Ernst, Graham Sutherland and Walt Disney.

Cuneo states that the painting is usually "considered in splendid isolation from its fifteen other companion pieces, based on the assumption that it either metonymically stands in for the entire cycle, or that its perceived aesthetic predominance merits exclusive focus.

[72] Reinhart Koselleck comments that Altdorfer's depiction of the thousands of soldiers was executed with "a mastery previously unknown",[65] and Kathleen Davis describes the painting as "epochal in every sense".