The name Eskisehir literally means "Old City" in Turkish. The city was founded by the Phrygians in at least 1000 BC, although it has been estimated to be older than 4000 years old. The current city lies about a mile from the ancient Phrygian city of Dorylaeum. Many Phrygian artifacts and sculptures can still be found in the city's archeological museum. There is also a museum of meerschaum stone, whose production remains still notable, used to make high quality meerschaum pipes. In the fourth century AD the city moved about ten km northeast, from Karacahisar to Sehirhöyük.

Many ancient geographers described the city as one of the most beautiful in Anatolia.

As with many towns in Anatolia, Christianity arrived after Constantine the Great legalized the religion in the Roman Empire. Beginning in the 4th century, records exist of bishops holding office in Eskisehir. The city was known as Dorylaeum in Greek in that period. One of these bishops, Eusebius, was heavily involved in shaping the evolving dogma of the church.

It was called Sultanönü during the Seljuk period. In 1097 it was the site of a battle in which the First Crusade defeated Kilij Arslan I; the town later fell to the Turks in 1176, or the 13th century.

Most of modern-day Eskisehir was rebuilt after the Turkish War of Independence (1919-1923), but a number of historic buildings remain, such as the Kursunlu Mosque. The archaeological site of the ancient Phrygian city of Dorylaeum is close to Eskisehir. The city is noted for its natural hot sulphur springs.