Alexander wasted no time in beginning plans for a Persian invasion. The expedition was his legacy, Philip's lifelong dream. Circumstances left the great Persian empire vulnerable at this opportune moment. Alexander also had more practical reasons for hurrying the mission along: he had inherited a considerable debt from Philip, and his army was expensive to maintain. While Alexander did manage to get by through further loans and gifts, the wealth of the Persian empire offered the best long-term solution to his financial problems.

The army that Alexander assembled was itself a marvelous achievement, described by modern military experts as technically and theoretically near-perfect. The land forces totaled almost 50,000, broken up into 43,000 infantry, 6,000 cavalry. Four main components made up the army: native Macedonian soldiers, troops delegated by cities of the League of Corinth, Greek mercenaries, and divisions from Balkan countries in alliance with or subject to Macedonia.

The Macedonian army itself was divided into four main units, each designed to complement the others. First was the phalanx, the main body of the army, organized in about fourteen battalions of 1,500 each, which would engage the enemy and attempt to create a break in its line. At this point the Companion Cavalry, heavily armed men on horses, would swoop in where breaks had been successfully created. The most elite group was known as the Hypaspists, who formed the King's personal corps and bodyguard. Totaling 3,000, they formed the link between the Companions and the phalanx by protecting one side of each while attempting to further exploit any gaps created. The less heavily armed Prodromi served as scouts, and they also protected outside flanks to prevent any attempts to encircle the Companions.

The number of troops Alexander demanded from the League was relatively small–the mission was clearly his and not some kind of Greek crusade. It is likely that he may have demanded these troops only as an attempt to ensure good behavior from the individual city-states while he was away. Many states, especially Athens, were reluctant to contribute. The largest component of the army consisted of mercenaries, who had good reason to expect a lucrative invasion, the Macedonian debt notwithstanding. Rounding out Alexander's troops were groups of archers and javelin throwers, representing Crete and Thrace.

The opposition they would face was a Persian army that drew on an imposing population of approximately fifty million people. In reality, however, the Persian forces were largely makeshift, poorly trained, and poorly equipped. Philip's death had made them even more complacent and lax. Ironically, the most reliable infantry in Persian employment were Greek mercenaries, who were estimated at about 30,000 at the start of the Macedonian expedition.

Alexander set out with his army in the spring of 334 B.C., with Parmenion serving second in command and Antipater left behind as a regent. The underlying purpose of the mission was to free the Greeks under Asia Minor and to avenge wrongs committed against Greece 150 years earlier. Furthermore, Alexander may have been the first commander in antiquity to organize a team officially dedicated to propaganda and publicity. Just as Homer had immortalized Achilles, Alexander appointed Callisthenes, a nephew of Aristotle, as the official historian of the Persian expedition. Alexander even made a stop in Ilium to make a sacrifice to Priam, the legendary King of Troy.

The first engagement took place at the Granicus River, where Alexander was very nearly killed from behind; his attacker was cut down at the last moment. The Macedonian discipline soon proved superior to the Persian, and the Greek mercenaries retreated to make offers of surrender. Alexander refused, however, and slaughtered the Greek mercenaries until only 2,000 remained alive. His severity was again meant to set an example, to discourage Greeks from serving as mercenaries for Persia. But this tactic may have had an opposite effect: by showing the mercenaries that they could expect no mercy, they felt that they had no choice but to fight to the finish. Moreover, Greeks at home likely felt more sympathy for their own kinsmen than the man who slaughtered them.

The overwhelming victory gave Alexander a considerable psychological edge, and soon several Persian satraps soon turned over their power without a fight. Many Greek cities that had been under Persian rule had their democracies restored, though their freedom had limitations; as they owed their restoration to Alexander, they were expected to pay a considerable tribute. One city in particular, Miletus, was significant because it served as a Persian naval base. Although Persia sent a considerable fleet, Alexander managed to reach Miletus first and take control of the harbor. He then succeeded in breaking the city walls, but this time he offered the Greek mercenaries a chance to surrender and join his forces; all gladly accepted the opportunity. Moreover, Alexander chose not to debase his greater mission by plundering the city.