The Isenach rises in the northern Palatinate Forest, 2 kilometres (1.2 mi) southwest of Carlsberg Hertlingshausen.

After the Isenach passes the Isenachweiher reservoir, it flows east through a valley it shares with Bundesstraße 37, Kaiserslautern-Bad Dürkheim.

In Bad Dürkheim, the Isenach breaks through the Haardt, the eastern edge of the Palatinate Forest, and enters the hills flanking the German Wine Road.

[citation needed] A dam was constructed in the Isenach in 1736–37 at about 5 kilometres (3 mi) from the source, forming a reservoir named the Isenachweiher.

This was necessary because until 1850 the pumps of the Bad Dürkheim Salt Works (also built in 1736) were operated using the Isenach as a source of water power.

However, when the city of Frankenthal had dug its Kanalhafen [de] ("Canal Harbour"), the Isenach and the Fuchsbach were diverted to fill it.

The Isenach was diverted further north, to its current mouth, which is about 8 kilometres (5 mi) from its original confluence with the Rhine.

The first public swimming facility in the town of Frankenthal was a pond-like widening of the Isenach, just outside the southern edge of the city, near the Post Bridge.

On a municipal level, the Isenbach is a responsibility of the Gewässer-Zweckverband Isenach-Eckbach ("Water District Isenach Eckbach"), which is subordinate to the Landkreis Bad Dürkheim.