Becoming king at the age of 43 in 336 B.C., Darius III quickly demonstrated his independence from his deadly benefactor. Bagoas tried to poison Darius as well, when he learned that even Darius couldn't be controlled, but Darius was warned and forced Bagoas to drink his own poison. The new king found himself in control of a vulnerable empire, large portions of which were governed by jealous and unreliable satraps and inhabited by disaffected and rebellious subjects. To make matters even worse for him, Philip II had now been granted permission by the Greeks to initiate a sacred war of vengeance against the Persians for desecrating and burning the Athenian Acropolis during the Second Persian War, over a century before. He sent an advance force into Asia Minor under the commands of his generals to liberate the Greeks in Ionia. They took the Greek cities of Asia from around the area of Troy, but Philip II was assassinated and his campaign was suspended while his heir, Alexander the Great, consolidated his control of Macedonia with the rest of Greece. Two years would go by and Darius III would do nothing to prepare.
In the Spring of 334 B.C., Alexander made his move at the head of an army of Macedonian and other Greek soldiers. This invasion, which marked the beginning of the Wars of Alexander the Great, was followed almost immediately by the victory of Alexander over the Persians at the Battle of Granicus. Darius III never showed up for the battle. He had no reason to suppose that Alexander intended to conquer the whole of Asia, and so he remained in Persepolis and required his satraps to handle the problem.
Darius did not actually take the field against Alexander until a year-and-a-half later, at the Battle of Issus in 333 B.C. His forces outnumbered Alexander's soldiers by at least 2 to 1, but Darius III was still outflanked, defeated, and forced to flee. It is told by the Greek historian Arrian that the moment the Persian army's left flank went to pieces under Alexander's attack, Darius fled leaving behind his chariot, his bow, and his royal mantle, all of which Alexander later picked up. He fled so fast that Alexander was able to capture his headquarters and take Darius' family as prisoners in the process. Darius petitioned to Alexander through letters several times to get his family back, but Alexander refused to do so unless Darius would acknowledge him as the new emperor of Persia. Alexander treated the captured women, Darius' wife, his mother, and two daughters, with great respect and would later marry one of the daughters.
Circumstances were more in Darius III's favor at the Battle of Gaugamela in 331 B.C. Having regrouped in Babylon, Darius now controlled 45,000 cavalry and 200,000 infantry, along with 200 chariots and 15 war elephants. The Macedonians had 31,000 heavy infantry, 9,000 light infantry, and 7,000 cavalry. While Darius had a significant advantage in numbers, most of the troops were of lower quality in comparison to Alexander's elite force. As a result, Darius III still fled the battlefield before any victor had been decided and deserted his experienced commanders, as well as one of the largest armies ever assembled. He would never be able to raise a large force against Alexander again. From this point forward, no one trusted him.
Darius III fled to Ecbatana while Alexander took Babylon, Susa, and the capital Persepolis. Darius III reportedly offered all of his empire west of the Euphrates River to Alexander in exchange for peace several times, each time denied by Alexander against the advice of his senior commanders. Alexander could have declared victory after the capture of Persepolis, but instead he decided to pursue Darius III. From Ecbatana, Darius III fled to Bactria with a small force of chariots and mercenaries. He led his army through the Caspian Gates, the main road through the mountains that would work to slow a following army. Persian forces became increasingly demoralized with the constant threat of a surprise attack from Alexander, leading to many desertions and eventually a coup led by Bessus, the satrap of Bactria, and Nabarzanes, one of the leaders of his cavalry who was also in charge of the palace guard. When Darius III would not relinquish his power, they eventually bound him and threw him in an ox-cart while they ordered the Persian forces to continue on. According to the Roman historian Curtius' History of Alexander, a small mobile force headed by Alexander arrived and threw the Persians into panic, leading Bessus, and two other conspirators, to wound the king with their javelins and leave him to die.
A Macedonian soldier found Darius either dead or dying in the wagon shortly thereafter – a disappointment to Alexander, who wanted to capture Darius alive. Alexander saw Darius' dead body in the wagon, and took the signet ring off the dead king's finger. Afterwards, he sent Darius' body back to Persepolis, gave him a magnificent funeral and ordered that he be buried, like all his royal predecessors, in the royal tombs.
After killing Darius III, Bessus took the regal name Artaxerxes V and began calling himself King of Asia. He was subsequently captured by Alexander, tortured, and executed. By the time Alexander fully conquered the Persian Empire, the Ancient Near East had captured his heart.
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