Epirus has been occupied since at least Neolithic times by seafarers along the coast and by hunters and shepherds in the interior who brought with them the Greek language. These people buried their leaders in large tumuli containing shaft graves, similar to the Mycenaean tombs, indicating an ancestral link between Epirus and the Mycenaean civilization. A number of Mycenaean remains have been found in Epirus, especially at the most important ancient religious sites in the region, the Necromanteion (Oracle of the Dead) on the Acheron river, and the Oracle of Zeus at Dodona.
The Dorians invaded Greece from Epirus and Macedonia at the end of the 2nd millennium BC (circa 1100–1000 BC), though the reasons for their migration are obscure. The region's original inhabitants were driven southward into the Greek mainland by the invasion and by the early 1st millennium BC three principal clusters of Greek-speaking tribes emerged in Epirus. These were the Chaonians of northwestern Epirus, the Molossians in the center, and the Thesprotians in the south.
The Molossian Aeacidae dynasty managed to create the first centralized state in Epirus from about 370 BC onwards, expanding their power at the expense of rival tribes. The Aeacids allied themselves with the increasingly powerful kingdom of Macedon, in part against the common threat of Illyrian raids, and in 359 BC the Molossian princess Olympias, niece of Arybbas of Epirus, married King Philip II of Macedon (r. 359–336 BC). She was to become the mother of Alexander the Great. On the death of Arybbas, Alexander the Molossian, uncle of Alexander the Great of Macedon, succeeded to the throne with the title King of Epirus.
In 334 BC, the time Alexander the Great crossed into Asia, Alexander I the Molossian led an expedition in southern Italy in support of the Greek cities of Magna Graecia against the nearby Italian tribes and the emerging Roman Republic. After some successes on the battlefield, he was defeated by a coalition of Italic tribes at the Battle of Pandosia in 331 BC.
In 330 BC, upon Alexander the Molossian's death, the term "Epirus" appears as a single political unit in the ancient Greek records for the first time, under the leadership of the Molossian dynasty. Subsequently, the coinages of the three major Epirote tribal groups came to an end, and a new coinage was issued with the legend Epirotes. After Alexander's I death, Aeacides of Epirus, who succeeded him, espoused the cause of Olympias against Cassander, but was dethroned in 313 BC.