After allowing more than one million migrants into Germany since 2015, sparking a strong backlash against immigration, Merkel has been battling for her political future.
The election campaign in prosperous Hesse, which includes Germany's financial centre of Frankfurt, has been largely overshadowed by the woes of a federal coalition in office only since March.
Over the last two weeks, voters in the states of Hesse and Bavaria also punished her party and coalition allies CSU and SPD in two separate regional elections. Social Democrat challenger Thorsten Schaefer-Guembel says "we are experiencing a crisis of confidence - that has a lot to do with the fact that too much waffling is going on and too little being done".
When Hesse last elected its state legislature in 2013 - on the same day that Mrs Merkel was triumphantly elected to a third term as chancellor - they won 38.3% and 30.7%, respectively.
Railing against the newcomers, the far-right anti-immigrant AfD is now the biggest opposition party in the Bundestag, and has seats in all of Germany's state parliaments.
The result means the anti-immigration party, which entered the federal parliament for the first time past year, is now also represented in all 16 German regional assemblies. Merkel's party managed an unimpressive win, narrowly salvaging a majority for its regional governing coalition with the Greens.
Observers believe Bouffier losing power or a disastrous result for Schaefer-Guembel would further destabilize Merkel's federal coalition.
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Nor did the veteran leader's fourth government get off to a good start after its formation earlier this year, with two rows over relatively minor points bringing it to the brink of collapse over the summer.
Several conservative party sources said that Friedrich Merz, a former parliamentary leader of Merkel's conservative alliance, was ready to put himself forward for the CDU chairmanship at the party's congress in December. The government's frailty has weakened her.
After leaders reluctantly agreed to a third right-left coalition earlier this year, the fourth Merkel government has staggered from one crisis to another, nearly collapsing twice over the summer in battles over relatively minor points.
Andrea Nahles, leader of the Social Democrats, on Sunday demanded a "clear, binding timetable" for implementing government projects before the coalition faces an already-agreed midterm review next fall.
As the country's two traditionally dominant centrist parties flailed in Hesse, forces on either flank surged: The far-right Alternative for Germany (AfD) and the progressive Greens.
Mrs Merkel's conservative CDU party now rules along with the centre-left Social Democratic Party (SDP). It has failed to convince voters that it's achieving much on other matters.