Eichsfeld was the only region of Thuringia not to accept the Protestant Reformation, largely due to the efforts of the Archbishops of Mainz.

In 1801, the clerical states were dissolved, and the Kingdom of Prussia gained the region, only to lose it again in the Napoleonic Wars.

In the Congress of Vienna (1815) Prussia as well as the Kingdom of Hanover raised claims for the Eichsfeld.

Although Hanover was annexed by Prussia in 1866, this border remained the boundary between two Prussian provinces, later between East and West Germany, and today between Thuringia and Lower Saxony.

The district is named after the historical region of Eichsfeld, which covers the northern portions of the present district and parts of Lower Saxony, the area around Duderstadt, called "Untereichsfeld" (lower Eichsfeld).