Pergamon was a city of northwestern Asia Minor. In the 4th century Pergamon was an important intellectual center where Aidesios taught Neoplatonic philosophy and "Chaldean wisdom" was popular. Maximus of Ephesus and Eunapius of Sardis worked there, and Julian came to study. Otherwise the city seems not to have flourished in late antiquity. Pergamon withdrew to its hilltop acropolis, fortified by Constans II, and became a city of the Thrakesion theme. It had an Armenian community and was the home of the emperor Philippikos. It was attacked by the Arabs in 663 and 716. After attacks by the Turks in 1109 and 1113, Pergamon was rebuilt by Manuel I around 1170 and probably became the capital of Neokastra. Pergamon fell to the Turks of Karasi soon after 1302.

It was one of the seven churches of the province of Asia listed in the Book of Revelations. It was a suffragan of Ephesus, elevated to metropolis in the 13th century. The Temple of Serapis - now known as the Red Hall - was first constructed as a temple during the Roman period, and was converted and used as a church during late Roman and Byzantine periods. One of its rotunda was used as a synagogue, and which then continued to be used but as a mosque beginning from 13th century onwards, making it a noteworthy example of the continuity of use for religious purposes at a particular place. Excavations reveal that the city of the 12th-13th century consisted of small houses, with a few public buildings and churches, built along narrow streets on the slopes of the acropolis. Theodore II Laskaris, who visited Pergamon before 1254, described the insignificance of the buildings of his day compared with the great works of antiquity. Pergamon preserves the remains of its two circuits of walls and of the medieval town.

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