The entire area of Aetolia and Acarnania has been inhabited at least since the Paleolithic era, as evidence such us tools made of pyrites have been found mainly near the lakes and rivers. Life continued during the Neolithic era as well. The first contact of the Aetolian and the Acarnanian with central Greece was due to the strategic location of the area on the sea-route Corinth-Corfu-Italy.

Under these circumstances the area got great cultural influence from Corinth, which established several trading activities along the coastline. The Athenian General, Demosthenes, invaded Aetolia in 426 BC, while by the end of the war the Spartan king Agesilaos invaded Acarnania in 389 BC.

Through these events a great hatred was created between the two sides. After the death of Alexander in 323 BC., the Athenians and Aetolians rebelled against the Macedonians, known as the Lamiakos war, ending in the victory of the Macedonian and Antipater. Unfortunately, the discord of the Greeks, allowed the active involvement of the Romans. The opposition of the Aetolians to the Macedonian-friendly Acarnanians, led to the signing of the Aetolian-Roman Pact in 212 BC.

Aetoloacarnania was a part of the Byzantine Empire from the 4th to the 12th century AC. Approximately in 1450 the west part of Central Greece was dominated by the Turks. In 1460 the last fort of Aetolian mainland, Aggelokastro, also surrendered. The revolution of 1821 was late to reach Aetoloacarnania due to the presence of great Turkish forces in Giannena. On May 5th, captain Dimitrios Makris attacked the Turkish outpost. The revolution is hastened, and Mesolonghi up rises on May 20th 1821. In April 1825 Kioutachis army siege of the last fort of the Revolution of Central Greece. His army was later on reinforced by Ibrahim of Egypt. The fall of the city with the "Exodus of its Guards" on April 10th 1826, virtually extinguished the flame of the Revolution.