Following his successful siege operations against Tyre and Gaza in 332 BCE, Alexander the Great temporarily turned aside from further conquest to organize his new territories and to solidify his lines of communication. The conquered peoples of Babylon and other places welcomed Alexander as a liberator, because of his reputation for leniency to those who surrendered and because he restored the temples the Persians had destroyed. During December 332 to March 331, Alexander absorbed Egypt and laid plans for the new city of Alexandria.

Alexander then marched back across the empire he had carved out of Asia Minor. This time, however, he moved directly against the distant cities of Persia, crossing the Euphrates on a bridge constructed by a detachment of his men under his general and lover, Hephaestion.

Persian king Darius III had not been idle. Since his defeat at Issus in 333, he had assembled a new army. Alexander had a maximum of 47,000 men: 31,000 heavy infantry (Phalangists) and 9,000 light infantry (Peltists), along with 7,000 cavalry. Ancient sources credit Darius with a force of between 200,000 and 1 million men. This is almost certainly an exaggeration, for maintaining a force this large would have been almost impossible given the primitive logistics of the time. Modern estimates place the total size of his army at no more than 100,000 men, of whom up to 40,000 were cavalry. By whatever measurement, Alexander's army was greatly outnumbered, but to him numbers meant little. Alexander's force was well-trained, well-organized, and disciplined, while Darius's was a polyglot force drawn chiefly from the eastern provinces, that included Persians, Medes, Babylonians, Syrians, Armenians, and Hindus.

Darius III and his great host awaited Alexander on the plain at Gaugamela, some 60 miles from the city of Arbela, (modern Erbil). The clash is sometimes erroneously known as the Battle of Arbela, since that was the nearest settlement. Most probably it took place east of the city of Mosul in northern Iraq.

Darius chose not to oppose Alexander's approach, trusting in superior numbers. Darius had selected the location so that he could make effective use of his superior numbers and employ his chariots, which had scythes mounted on their wheel hubs to cut down Alexander's forces. Some sources contend that Darius had the plain cleared of vegetation for ease of maneuver. Darius was confident his preparations would bring him victory.

Alexander moved slowly to Gaugamela, hoping to wear down the defenders and exhaust their food stocks. When Alexander finally arrived, his chief of staff, Parmenio, urged a night attack to offset the numerical disadvantage, but Alexander refused. Apart from the difficulty of maintaining control at night, Alexander opposed any effort to "steal victory like a thief." He would, he said, "defeat his enemies openly and honestly." As it turned out, Darius had feared a night assault and kept his troops awake all night. The next morning the men were exhausted, while Alexander's men were well rested.

Battle was joined on October 1, 331. Alexander, who fought with his Companion cavalry, commanded the right flank of his army, while Parmenion had charge of the left. Macedonian and Greek cavalry protected the two flanks. Alexander arranged the army in oblique formation, refusing his left and moving the army laterally to the right across the Persian front. His plan was to draw the Persians to the flanks, opening a weak point in the center of the Persian line. Everything depended on his flanks holding until Alexander could detect this weakness and strike a decisive blow.

Darius positioned himself in the center of the Persian line with his best infantry. Bessus commanded the cavalry on the Persian left wing with chariots in front, while Mazaeus commanded the right flank of other cavalry. With their vast superior numbers of cavalry and much longer line, it appeared that the Persians must inevitably flank Alexander's army.

Darius ordered Bessus to release cavalry to ride around the Macedonian right wing and arrest Alexander's movement. Bessus committed some 11,000 cavalry to the effort, but they were halted by the numerically far inferior force of Macedonian cavalry and Greek mercenary infantry. Clearly Alexander's cavalry was far better disciplined and more closely knit than Persia's local detachments, which had never trained together.

Darius ordered the 100 chariots positioned in front of his left wing to attack Alexander's elite force of Companion cavalry on the Macedonian right. Alexander's infantry screen of javelin throwers, archers, and light infantrymen somewhat blunted the Persian chariot charge before it reached the Companions. The Companions then wheeled aside, allowing the remaining chariots to pass through unopposed, when they came up against the lances of the infantry. The gap then closed and the Persian charioteers were annihilated in the Macedonian rear.

Darius then ordered a general advance. Mazaeus, who commanded the Persian right wing, advanced against the Macedonian left led by Parmenion. He also sent cavalry in an attempt to get around the Macedonian line. At the same time, Bessus sought to push men around the Macedonian right wing to envelop it. These efforts by Bessus and Mazaeus elongated the Persian line as Alexander had hoped, weakening its center. Mazeaus's job was especially difficult, as his men had to travel a greater distance to engage Alexander's refused left wing.

Alexander watched for weakness in the Persian line, bringing up his reserves. Once he detected it, he led his Companion cavalry and light infantry in a great wedge-shaped formation into the breach. Twice the Macedonians burst through gaps in the Persian line and drove close to where Darius's chariot stood. Both Persian flanks were now threatened by the great gap the Macedonians had torn in the center of the line.

The possibility of encirclement led Bessus to retreat, his forces suffering heavy casualties at the hands of the pursuing Macedonians. Darius, now himself in danger of being cut off, panicked and fled. With the Persians in wild retreat, the Macedonians vigorously pressed their advance, scattering the vast Persian host.

Alexander's left wing, heavily engaged with Mazaeus's men, could not keep pace with the rest of the Macedonian advance. Alexander's attempt to encircle Mazaeus failed, however, because his own cavalry drove the Persians back too quickly. The victory was nonetheless sweeping. The Macedonians reported their casualties in the battle at some 500 killed and up to 3,000 wounded, while setting Persian losses at close to 50,000.

Bessus and other Persian generals murdered Darius. Alexander later caught such regicides as he could and executed them. Alexander did not rest but after the battle advanced rapidly toward the Persian capital of Persepolis so as not to allow the Persian generals time to reorganize their forces.

Alexander sent most of his men by the long route, while he led about a third of his force through the mountains on a short route through the Persian Gates (the strategic pass now known as Tang-e Meyran, in modern Iran), held by a Persian army under Ariobarzan. The Persians halted the Macedonians at the narrow pass and reportedly inflicted heavy casualties on them. Either through a shepherd or prisoners, Alexander learned of a path that flanked the Persian position. In a highly dangerous move, Alexander and a number of his men traversed it at night and turned the Persian position. As a result, Alexander reached Persepolis before the guards of the treasury could secret its reputed 3,000 tons of gold and silver, the greatest treasury in the world. He then destroyed the great palace, perhaps as a sign of the end of Persian power.

Alexander was now 25. In four years, he had broken the power of Persia forever and ruled an empire of 1 million square miles. No one in the world could come close to him in wealth or power. The speed of what he accomplished stands unequaled before or since. He had no intention of resting on his laurels though. He continued his conquests, reaching the steppes of Russia to the north and India to the south, before his soldiers would go no further. Alexander died in Babylon, following a drinking bout, in 323.

Among the many riddles of Alexander's life is his failure to provide for a successor. Only in the last year of his life did he beget an heir, who was too young to prevent a struggle for the throne. As Alexander lay dying, one of his generals asked to whom he left the throne. Reportedly Alexander whispered, "Kratisto" (to the strongest). His empire was divided among his generals and his vision of a universal commonwealth was lost.