The city of Kayseri has been continuously inhabited since the establishment nearby of the ancient Hittite trading colony at Kultepe in approximately 3000 BCE.
The city has always been a vital trade centre as it is located on major trade routes, particularly along what was called the Great Silk Road. Known as Mazaca, Kayseri served as the residence of the kings of Cappadocia. In ancient times, it was on the crossroads of the trade routes from Sinop to the Euphrates and from the Persian Royal Road that extended from Sardis to Susa. In Roman times, a similar route from Ephesus to the East also passed through the city.
The city stood on a low spur on the north side of Mount Erciyes (Mount Argaeus in ancient times). Only a few traces of the ancient site survive in the old town. The city was the centre of a satrapy under Persian rule until it was conquered by Perdikkas, one of the generals of Alexander the Great when it became the seat of a transient satrapy by another of Alexander's former generals, Eumenes of Cardia. The city was subsequently passed to the Seleucid empire after the battle of Ipsus but became once again the centre of an autonomous Greater Cappadocian kingdom under Ariarathes III of Cappadocia at around 250BC. In the ensuing period, the city came under the sway of Hellenistic influence, and was given the Greek name of Eusebia in honor of the Cappadocian king Ariarathes V Eusebes Philopator of Cappadocia (163–130 BCE). Under the new name of Caesarea, by which it has since been known, given to it by the last Cappadocian King Archelaus or perhaps by Tiberius, the city passed under formal Roman rule in 17BCE.
Caesarea was destroyed by the Sassanid king Shapur I after his victory over the Emperor Valerian I in 260. At the time it was recorded to have around 400,000 inhabitants. The city gradually recovered and, indeed, became a home to several early Christian saints: saints Dorothea and Theophilus the martyrs, Gregory of Nazianzus, Gregory of Nyssa and Basil of Caesarea. In the 4th century, bishop Basil established an ecclesiastical centre on the plain, about one mile to the northeast, which gradually supplanted the old town. In it Basil included a system of almshouses, an orphanage, old peoples' homes and a leprosarium, a leprosy hospital. A portion of Basil's new city was surrounded with strong walls and turned into a fortress by Justinian. Caesarea became in the 9th century a Byzantine administrative centre as the capital of the Byzantine Theme of Charsianon.
The Arab general (and later the first Umayyad Caliph) Muawiyah invaded Cappadocia and took Caesarea from the Byzantines temporarily in 647. The city was called Kaisariyah by the Arabs and later Kayseri when it was captured by the Seljuk sultan Alp Arslan in 1064. It became one of the most prominent centers of initially the Danishmendids (1074–1178), and later the Anatolian Seljuk Sultanate (1178–1243), until it fell to the Mongols in 1243. Within the walls lies the greater part of Kayseri rebuilt between the 13th and 16th centuries. The city became Ottoman in the 15th century.
Thus, there were three golden-age periods for Kayseri. The first, dating back to 2000 BCE, was when the city was a trade post between the Assyrians and the Hittites. The second golden age came during the Roman rule (1st-11th C). The third golden age was during the reign of Seljuks (1178–1243), when the city was the second capital of the state.
The 1500-year-old castle, built initially by the Byzantines and expanded by the Seljuks and Ottomans, is still standing in good condition in the central square of the city. The short-lived Seljuk rule left large number of historical landmarks; historical buildings such as the Hunad Hatun Mosque complex, Kilij Arslan Mosque, The Grand Mosque and Gevher Nesibe Hopital. The Grand Bazaar dates from the latter part of the 1800s, but the adjacent caravanserai (where merchant traders gathered before forming a caravan) dates from around 1500. The town's older districts (which were filled with ornate mansion-houses mostly dating from the 18th and 19th centuries) were subjected to wholesale demolitions starting in the 1970s. The city is famous for its carpet sellers, and a range of carpets and rugs can be purchased reasonably ranging from new to 50 or more years old.
In the 4th century the city became central to early Christianity when St. Basil the Great established an ecclesiastical centre here. It is a Roman Catholic titular see and was the seat of an Armenian diocese.
The building that hosts the Kayseri lyceum was arranged to host the Turkish Grand National Assembly during the Turkish War of Independence when the Greek army had advanced very close to Ankara, the base of the Turkish National Movement.