In the summer of 336 b.c.e., Phillip was assassinated, and Alexander gained the Macedonian throne. Alexander then found himself surrounded by enemies from near and far, and disposed of these people by ordering their execution. He marched on Thessaly, and restored Macedonian rule. By the end of the summer in 336 b.c.e. he had re-established his position in Greece, and was elected head of the Greek forces for a war against Persia by a congress of states in Corinith. Alexander began his war against Persia in the spring of 334 b.c.e. with an army of 35,000 troops from Macedonia and Greek City states. Near the ancient city of troy (modern-day Turkey), he attacked an army of 40,000 Persian and Greek mercenaries. After this battle, Asia submitted to him.

Continuing to advance southwards, Alexander encountered the main Persian army under King Darius III, at Issus, in northeastern Syria. The battle of Issus in 333 b.c.e. ended in a great victory for Alexander. Tyre, a strongly fortified seaport, offered obstinate impeding, but Alexander took it by storm in 332 b.c.e. after a siege of seven months. Alexander captured Gaza next, and then passed on into Egypt. As a result of these successes, he secured control of the entire east Mediterranean coastline. Later in 332 b.c.e. he founded, the city of Alexandria.

Alexander started for Babylon; he reorganized his forces and left with an army of 40,000 infantry and 7,000 cavalry. He met Darius at the head of the Persian army, which, was said to number a million men, Alexander defeated the Persians at the Battle of Gaugamela, on October 1, 331 b.c.e. Babylon surrenders after Gaugamela, and the city of Susa with its enormous treasures was conquered soon afterwards. Then, Alexander forced his way to Persepolis, the Persian capital; he burned the city, and thus completed the destruction of the ancient Persian Empire. He's field now extended along and beyond the southern shores of the Caspian Sea, Russian Turkistan, it had taken Alexander only 3 years, to master this vast area.