Del Ponte quit in protest at the lack of follow up action from the UN Security Council to a dozen reports it has produced on serious human rights abuses and war crimes during the six-year conflict.
Guterres regrets her decision to resign but stresses the "importance of accountability for crimes against civilians during the conflict," UN spokesman Stephane Dujarric told reporters.
"He supports the continued work of the commission as an important and integral part of the accountability process," he added.
Del Ponte had been working on the commission since September 2012.
The 70-year-old Swiss national has also worked to uncover war crimes in Rwanda and in the former Yugoslavia.
Established by the UN Human Rights Council, the commission is tasked with reporting on serious rights violations and war crimes in Syria, where more than 330,000 people been killed since the start of the war in March 2011.
The commission has repeatedly urged the Security Council to ask the International Criminal Court to open an investigation for war crimes in Syria.
A bid by the council in 2014 to refer Syria to the ICC was blocked by China and Russia, Syria's ally.
"I cannot remain on this commission that does absolutely nothing," Del Ponte told the Swiss newspaper Blick, accusing members of the Security Council "of not wanting to establish justice."
"At first there was good and bad -- the opposition on the side of good and the government in the bad role," she said.
Today, "everyone in Syria is on the bad side. The (Bashar al) Assad government has perpetrated horrible crimes against humanity and used chemical weapons. And the opposition is now made up of extremists and terrorists."
She added that she had never seen such crimes committed elsewhere, not in the former Yugoslavia or Rwanda.
Frustrated by the Security Council's inaction on Syria, the UN General Assembly last year set up an international panel to help collect evidence to be used in future cases of war crimes prosecution.
Catherine Marchi-Uhel, a French judge who has tried international cases in Kosovo, Cambodia and the former Yugoslavia, is to begin work as the head of the new panel in Geneva on Tuesday.