The sudden departure of Marie Collins, an outspoken Irish woman who was the last remaining survivor of priestly abuse on a Holy See commission, was a major setback for the Pope, who has faced criticism of not doing enough to tackle the problem.
The work of the Pontifical Commission for the Protection of Minors, set up by Francis in March 2014, has been slowed down by internal disputes and Ms Collins blamed the Vatican's administration, known as the Curia, for the "constant setbacks".
"The lack of cooperation, particularly by the dicastery most closely involved in dealing with cases of abuse, has been shameful," she said in a statement.
She said the Pope had a "genuine wish" to solve the problem, but in later comments to a Catholic publication she criticised him for being too forgiving towards sexual abuse in the Church.
She told the National Catholic Reporter that in her three years on the commission she had never been able to speak to the pontiff, and denounced those who surround him.
"It is devastating in 2017 to see that these men still can put other concerns before the safety of children and vulnerable adults," she said, listing a string of cases in which she said the commission's work had been hampered by Church officials.
The Vatican said the Pope had accepted her resignation "with deep appreciation for her work on behalf of the victims/survivors of clergy abuse".
Cardinal Sean O'Malley of Boston, who heads the commission, also thanked her for her work and said the commission would look at her concerns at a meeting next month.
"It is a reflection of how this whole abuse crisis in the Church has been handled: with fine words in public and contrary actions behind closed doors," she said.
Thousands of cases of sexual and physical abuse of youths by priests have come to light around the world in recent years as investigations have encouraged long-silent victims to finally go public with their complaints.
Victim support groups have repeatedly attacked the Vatican for its response to the crisis since it first emerged in the US in 2002, saying successive Popes have failed to grasp the gravity of the situation.
While acknowledging Pope Francis's good intentions on ending sex abuse, Ms Collins said he was misguided and ineffective.
"I feel (he) does not appreciate how his actions of clemency undermine everything else he does in this area," she said, referring to a recent report that the pope had reduced sanctions against several paedophile priests who had sought clemency.
In February last year, Briton Peter Saunders, the only other member of the commission who had suffered clerical sexual abuse, left to take a leave of absence after repeatedly criticising the commission's work. It is unclear if he will return.
Mr Saunders and Ms Collins both threatened to resign as long ago as February 2015 unless bishops were made more accountable over cover-ups of rampant sexual abuse or failing to prevent it.