According to mythology, it was built by king Agrios, son of Portheus and a great grandson of Aetolos (king of Plevron and Calydon) around 1600-1100 BC. The town, built near the banks of river Achelous (the natural border between Aetolia and Acarnania), was claimed by both states during ancient times. Agrinio became member of the Aetolian League and it was later destroyed by Cassander in 314 BC during the League's wars against the Kingdom of Macedonia.
The city reappears during the Ottoman period with the name Vrachori and apart from its Greek population it was also inhabited by many Turks. In 1585 it was deserted during the revolt of Theodoros Migas. At the beginning of the 18th century it became the administrative centre of Aetolia-Acarnania (then as the sanjak of Karleli), depended on the imperial harems. Vrachori participated in the Greek Revolution and was temporarily liberated on June 11, 1821. On August 1822, while Reşid Mehmed Pasha's (Kütahi) troops were marching towards Vrachori, its citizens decided to burn and evacuate their city, following the strategy of scorched earth. The deserted city was recaptured by the Turks. The city was finally included in the borders of the newborn Greek state permanently in 1832 with the treaty of Kalendar Kiosk (July 9, 1832) and was renamed after its ancient name, Agrinion.
In the years following the liberation, Agrinio went through an important growth and development, especially at the end of the 19th century and the dawn of the 20th. After the Greco-Turkish War and the Asia Minor Catastrophe, many refugees from Asia Minor (western Turkey) arrived in the city and settled in the district of Agios Konstantinos. At the same period there was an important internal immigration to Agrinio from the whole Aetolia-Acarnania region, along with immigration from the areas of Epirus and Evrytania.
During the Interwar period, in spite of economical crisis, works of infrastructure took place in the city, like the paving of streets and the installment of electricity, while a water tower was installed in 1930. At the same time excavations revealed the ancient city of Agrinion. Growth and prosperity returned after World War II and the Greek Civil War. This growth was boosted by the building of two major hydroelectric dam installations at Kremasta and Kastraki, on the north of the city. The tobacco industry and olive tree cultivation became the main income sources of the city.