To complete his conquest of the Persian Empire, Alexander then crossed the Indus River in 326 b.c.e., and invaded the Punjab as far as the river Hyphasis. He then sailed down the Hydaspes, where he defeated the Indian ruler Porus in 326 b.c.e., to the Indus, reaching its delta in September 325 b.c.e. Then he proceeded to the Persian Gulf. Alexander marched overland to Susa which he reached in 324 b.c.e. He arrived in Babylon in the spring of 323 b.c.e., but in June contracted a fever and died. He left his empire, "to the strongest"; this ambiguous testament resulted in dire conflicts for half a century.

Alexander was one of the greatest conquerors in history, noted for his brilliance as a tactician and leader of men and for the speed with which he traverse great expanses of territory. He arranged for 30,000 young Persians to be trained in Greek speech, Macedonian tactics, and enrolled them in his army. He himself adopted Persian manners. Shortly before he died, Alexander ordered the Greek cities to worship him as a God. Although he probably gave the order for political reasons, he was, in his own view and that of his contemporaries, of divine birth.

Alexander founded a number of cities, along his line of march. Greek veterans from his army settled in them; young men, traders, merchants, and scholars were attracted to them; Greek culture was introduced and the Greek language became widely known. Alexander vastly extended the influence of Greek civilization and prepared the way for the kingdoms of the Roman Empire.