The leader of France's centre-right Les Républicains party announced he would step down on Sunday just one week after his party received its lowest score ever in the European elections.
The party received just 8.48% of the vote in France on May 26 whereas, in 2014, the party received 20.41% of the vote.
"The election was a failure," Wauquiez told the French channel TF1 on Sunday. "It's not easy but we must humbly recognise that it was a failure."
"Victories are collective. Defeats are solitary. That's the way it is," Wauquiez continued.
Wauquiez went on to say that he must take responsibility and that he had given the decision serious consideration.
Pressure had been mounting on the 44-year-old right-wing politician to resign from the post he has held for 18 months.
The Républicains president of the Ile-de-France region, Valérie Pécresse, told RTL the day after the European elections that if she were in Wauquiez's place, she would resign.
Eleven young Les Républicains deputies posted a statement on Twitter Thursday stating that French people no longer voted or believed in the party's ideas and called for a renewal committee to voice a new generation of the party.
Les Républicains — previously known as the Union for a Popular Movement (UMP) — is the same party of former French president Nicolas Sarkozy and former Prime Minister Alain Juppé. It is also the former party of Macron's prime minister Édouard Philippe.
Les Républicains presidential candidate François Fillon came in third place in the first round of the 2017 election behind Emmanuel Macron and Marine Le Pen.
But the party was in fourth place behind Marine Le Pen's far-right National Rally, Macron's En Marche party, and Yannick Jadot's Green Party list in the European elections.
Wauquiez will now focus on his role as president of the region Auvergne-Rhône-Alpes.