"I cannot accept being undermined as head of the paper," Nougayrede said in her resignation letter on Wednesday.
She no longer has the authority to do her job with the "peace of mind and serenity" necessary, she said.
On Friday her two deputies, who have also been criticised by a large part of the newsroom, stepped down.
The junior editors claim that Nougayrede, who replaced the highly respected Erik Izraelewicz who died of a heart attack in November 2012, is “very difficult to talk to”, an anonymous source told the AFP news agency.
Centre-left Le Monde had a circulation of 330,000 last year, slightly lower than right-wing Le Figaro.
It has been expanding its website but many staff criticise management’s handling of the transition.