After his invasion of Gallia, Gaius Iulius Caesar made the Rhine river the border between the Roman Empire and Germania.

Having been nearly destroyed in the times of the plague and the Thirty Years' War, during which it was conquered by Austria and then by France,[3] Germersheim was burned down by French troops in 1674.

The death of the childless elector Charles II in 1685 led to the devastating War of the Palatinate Succession (1688-1697) during which Germersheim was claimed by the French as a dependency of Alsace.

Through the intervention of the pope in 1702, the French, on payment of a large sum, agreed to vacate the town, and in 1715 its fortifications were rebuilt.

Germersheim was the scene of several conflicts between French troops and German veteran associations during the occupation of the Rhineland following the First World War.

General Hans Graf von Sponeck, who ordered the retreat of his troops from Kerch because they were going to be hopelessly cut off by the Russian landings at Theodosia on the Crimean peninsula, and against express instruction of his superior officer in the winter 1941, was interned here in the fortress after Hitler had commuted his death sentence to six years' detention.