Alexander embarked on his expedition to conquer the Persian Empire in the spring of 334 BC,^[8] having pacified the warring Greek states and consolidated his military might.^[9] During the first months of the Macedonian passage into Persian Asia Minor, Darius III – king of Persia – largely ignored the presence of Alexander's 40,000 men. The Battle of the Granicus, fought in May,^[8] was Persia's first major effort to confront the invaders, but resulted in an easy victory for Alexander. Over the next year, Alexander took most of western and coastal Asia Minor by forcing the capitulation of the satrapies in his path.^[10] He continued inland, travelling northeast through Phrygia before turning southeast toward Cilicia. After passing the Cilician Gates in October, Alexander was delayed by fever in Tarsus.^[11] Darius, meanwhile, mustered an army of up to 100,000 (some ancient sources posit exaggerated figures of over 600,000)^[12] and personally directed it over the eastern slopes of the Amanus Mountains. In early November, as Alexander proceeded about the Gulf of Issus from Mallus via Issus, the two armies inadvertently passed one another on opposite sides of the mountains.^[13] This was decidedly to Darius' advantage: now at the rear of Alexander, he was able to prevent retreat and block the supply lines Alexander had established at Issus.^[14] It was not until Alexander had encamped at Myriandrus, a seaport on the southeastern shores of the Gulf of İskenderun, that he learned of the Persian position. He immediately retraced his route to the Pinarus River, just south of Issus, to find Darius' force assembled along the northern bank.^[13] The Battle of Issus ensued.

The initial dispositions at the Battle of Issus. The Pinarus River separates the belligerents, and Issus is 7 miles (11 km) to the north. Cavalry is concentrated on the shores of the Gulf of İskenderun (or Gulf of Issus) on both sides. Alexander devotes himself to a right approach with his Companion cavalry, having unseated the Persian foothill defence.

Darius' initial response was defensive: he immediately stockaded the river bank with stakes to impede the enemy's crossing. A core vanguard of traitorous Greek mercenaries and Persian royal guard was established; as was usual for Persian kings, Darius positioned himself in the centre of this vanguard, in order that he might effectively dispatch commands to any part of his large army.^[15] A group of Persian light infantry was soon sent to the foothills, as it was suspected that Alexander would make an approach from the right, away from the coast. A mass of cavalry commanded by Nabarsanes occupied the Persian right.^[16]

Alexander made a cautious and slow advance, intending to base his strategy on the structure of the Persian force. He led a flank of his Companion cavalry on the right, while the Thessalian cavalry were dispatched to the left, as a counter to Nabarsanes' mounted unit.^[17] Aware of the importance of the foothills to his right, Alexander sent a band of light infantry, archers, and cavalry to displace the defence Darius had stationed there. The enterprise was successful – those Persians not killed were forced to seek refuge higher in the mountains.^[17][18]

When within missile range of the enemy, Alexander gave the order to charge.^[17][19] He spearheaded the assault of his heavily armed Companion cavalry, who quickly made deep cuts into the Persian left flank. The Macedonian left wing, commanded by Parmenion,^[18] was meanwhile driven back by Nabarsanes' large cavalry. The Macedonians' central phalanx crossed the river and clashed with the renegade Greek mercenaries who fronted Darius' vanguard. As the Companion cavalry pushed further into the Persian left, the danger arose that Darius would exploit the gap that had formed between Alexander and the rest of his army. 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. Unable to handle the added pressure, the Persian vanguard was forced to withdraw from the river bank, allowing the Macedonian phalanx to continue their advance and lifting the pressure on Parmenion's left wing.^[19]

Upon realising that the onslaught of Alexander's Companion cavalry was unstoppable, Darius and his army fled. Many were killed in the rush, trampled by those who fled with them or collapsed with their horses.^[20] Some escaped to regions as remote as Egypt, and others reunited with Darius in the north.^[21] The onset of darkness ended the chase after approximately 20 km (12 mi); Alexander then recalled his army and set about burying the dead. Darius' family were left behind in the Persian camp; it is reported that Alexander treated them well and reassured them of Darius' safety.^[21][22] Darius' royal chariot was found discarded in a ditch, as were his bow and shield.^[21]

Ancient sources present disparate casualty figures for the Battle of Issus. Plutarch and Diodorus Siculus approximate 100,000 Persian deaths, in contrast with the 450 Macedonian deaths reported by Quintus Curtius Rufus.^[23] In any case, it is probable that more Persians were killed as they fled than in battle;^[24] Ptolemy I, who served with Alexander during the battle, recounts how the Macedonians crossed a ravine on the bodies of their enemies during the pursuit.^[23][25]

The Macedonian conquest of Persia continued until 330 BC, when Darius was killed and Alexander took his title as king.^[26] Alexander died in 323 BC, having recently returned from campaigning in the Indian subcontinent. The cause of death remains a subject of debate.^[27][28]