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Karkamış is an ancient city whose history goes back several thousand years. It is the traditionnal location of a Euphrate river crossing point, along with Birecik, about 20km to the North. Coming from Alep, Karkamış was an obvious choice for the builders of the Baghdad Railway.

Karkamış was reached by rails at the end of 1912 and was a terminal station for the duration is took to build the bridge over the Euphrate. It seems that a provisional wooden bridge was open to traffic in July 1914, to be replaced lated by the 10 spans steel bridge still in place today.

In 1960, Karkamış became a junction station with the opening of the new route via Gaziantep instead of via Alep. This became the main line and the line from Alep lost most traffic.

Karkamış has a small engine shed and a turntable. The shed is currently out of use and partially demolished. It seems it was abandoned soon after the end of steam, in the early 1990s.