Siewert took over as interim coach after the departure of Bo Svensson in November and was made permanent boss shortly before Christmas.
The former Huddersfield manager served just 12 games in charge of Mainz, winning once and drawing six times.
That one victory remains Mainz's only league win of the season. The side sit second-last, ahead of bottom club Darmstadt on goal difference.
Sporting director Christian Heidel "thanked Jan for his commitment" but said "his impetus was not reflected in a fundamental turnaround or results."
Mainz are known for taking chances on young but promising coaches, having given both Jurgen Klopp and Thomas Tuchel their first senior head coaching jobs.
A former player with the club, Klopp took Mainz to their first-ever promotion to the top division in 2004.
