The place was an ancient city of Cilicia, which controlled a passage from eastern Anatolia to the north Syrian plain.

It became an important Neo-Hittite center after the collapse of the Hittite Empire in the late 12th century BC.

The site's eighth-century BC bilingual inscription, in Phoenician and Hieroglyphic Luwian, reflects the activities of the kings of Adana from the "house of Mopsos", given in Hieroglyphic Luwian as mu-ka-sa- (often rendered as 'Moxos') and in Phoenician as Mopsos in the form mpš.

He acknowledged himself as a subordinate of Awariku, the king of Adanawa (Adana), which was the ancient kingdom of Quwe.

[7] Karatepe was excavated from 1947 to 1957 by a team led by Helmuth Theodor Bossert (1889–1961), revealing the ruins of the walled city of king Azatiwataš.

In the late 1990s, archaeological work, now led by Halet Çambel (1916–2014), was conducted on a palace at the site.

[13] In the 2004 exploration of Mars, "Karatepe" was the name given to a site designated for entering the Endurance Crater to investigate the layering of the bedrock.

The archaeological site of Domuztepe (Aslantaş) is located on the eastern bank of Ceyhan river, across from Karatepe.