Alexander's specific goals in Asia were several. Officially, he was leading a Panhellenic invasion of the Persian Empire to rid the world of tyranny and oppression, and he also sought revenge on the Persians for their invasion of Greece in 490 B.C.E. Alexander, however, conquered lands outside of the Persian Empire because he had a personal longing to see the Ocean that was believed to encircle Europe and Asia at the edge of the Earth.

When he crossed the Hellespont with his army in 334 B.C.E., Alexander threw his spear from his ship to the coast and it stuck in the ground. He stepped onto the shore, pulled his weapon from the soil, and declared that the whole of Asia would be won by the spear. Also significant about Alexander's crossing of the Hellespont into Asia Minor was that he landed at Troy just like Achilles had done in Homer's Iliad.

The Macedonian army soon encountered the Persian army under King Darius at the crossing of the river Granicus, near the Aegean coast. Alexander courageously plunged his cavalry into the swiftly flowing river and fought his way up the steep riverbank to meet the Persians, who were defeated in fierce hand-to-hand combat.

Alexander proceeded to march south through Ionia and free the Greek cities there from Persian rule, and thus, he confirmed his status as the great liberator of civilized men. Then he turned northward to Gordion, home of the famous Gordian Knot. The legend behind the ancient knot was that the man who could untie it was destined to rule the entire world. Alexander simply slashed the knot with his sword and unraveled it.

In November of 333 B.C.E., Alexander met Darius in battle for the second time at a mountain pass at Issus. Although the Persian army greatly outnumbered the Macedonians, the narrow field of battle allowed Alexander to defeat the Persians, even though Darius escaped. Following the battle, Alexander entered Damascus and captured Darius' war chest and his family. In the next year, he marched down the Phoenician coast and received the surrenders of all of the major cities there except for Tyre. A seven-month siege of the city followed, and the Tyrians eventually surrendered to Alexander. Then he continued south into Egypt after he had secured the entire Aegean coast.

Alexander left Egypt in 331 B.C.E. in pursuit of Darius. He conquered the lands between the rivers Tigris and Euphrates and found the Persian army at the plains of Gaugamela. The Macedonians spotted the lights from Persian campfires one night, and the encouraged Alexander to lead his attack under cover of darkness. He refused to take advantage of their situation because he wanted to defeat Darius in an equally matched battle so that the Persian king would never again dare to raise an army against the Macedonians. The two armies met on the battlefield the next morning, and the Macedonian forces swept through the Persian army and slaughtered them. Alexander nearly captured Darius, but he was prevented from doing so by strategic bungling on the part of Parmenio, the Macedonian general on the right wing. After this decisive victory, Alexander was named King of Asia, and he sent letters to all of the Greek cities proclaiming that he had rid Asia of tyranny.

Then Alexander turned south and obtained the surrenders of Babylon and Susa and acquired vast riches from those cities. Then he fought his way into Persepolis, the capital of the Persian Empire, and stayed there for several months to rest his army. After four months, the Macedonians burned the royal palace to the ground. Some historians say that this was done to avenge the Persian invasion of Greece in 490 B.C.E., but others hold that the fire was set at the suggestion of an Athenian woman, Thais, at one of Alexander's drinking parties, immortalized in poetry by John Dryden.

In 330 B.C.E., a series of allegations was brought against some of Alexander's officers concerning a plot to murder him. Alexander tortured and executed his friend, Philotas, the accused leader of the conspiracy, and several other high-ranking officials in order to eliminate the possibility of an attempt on his life. This incident contributed greatly to the paranoia that grew in Alexander throughout his career. Later in the same year, after a long evening of feasting and heavy drinking, a fierce argument arose between Alexander and his life-long friend and companion, Cleitus. After unchecked taunting by Cleitus, Alexander ran him through with a spear. Although he mourned his friend excessively and nearly committed suicide when he realized what he had done, all of Alexander's associates thereafter feared his paranoia and dangerous temper.

Alexander continued his pursuit of Darius for hundreds of miles from Persepolis. When he finally caught up to him, he found the Persian king dead in his coach, assassinated by his own men. Alexander had the assassins executed and gave Darius a royal funeral.

As the Macedonians marched into Parthia, the tone of the journey changed. Alexander had adopted the Persian style of dress, rather than his traditional Macedonian clothing, and his troops were unhappy with him. They gradually became more reluctant to follow him, but his charismatic personality persuaded them not to abandon him. The change in Alexander's attire was but one part of his grand effort to reconcile Greek and Persian culture. He established training programs to teach Persians about Greek and Macedonian culture, and he even married a Persian dancer named Roxane.

In the spring of 327 B.C.E., Alexander and his army marched into India.