In 334 BC the Macedonian king Alexander III (reigned 336-323 BC) led his forces into Asia. At the River Granicus he routed a Persian army before capturing the coastal cities of western Anatolia. Moving inland in 333 BC he reached Gordian and continued towards Syria where, at the Battle of Issus, the Persian forces under Darius III (reigned 336-332/330 BC) were defeated. Alexander advanced along the Mediterranean coast in 332 BC capturing the Phoenician cities before moving into Egypt where he was crowned as Pharaoh. The following year Alexander returned to the Levant and into north Mesopotamia. At Gaugamela he again defeated Darius III and advanced to Babylon and Susa.

By 330 BC Alexander had reached the Persian capital of Persepolis, which he sacked. Pursuing Darius III, who was murdered, Alexander marched on through the Hindu Kush and across the River Oxus. India was invaded in 327 BC but the following years saw Macedonian mutiny and loss of life on the return journey from India through southern Iran. In June 323 BC Alexander fell ill at Babylon and died. The Persian Empire had been conquered by Alexander but it was to be his generals who divided and ruled the vast territories.