The 65-year-old former chief prosecutor on both the International Criminal Tribunal for the former Yugoslavia (ICTY) and the International Criminal Tribunal for Rwanda (ICTR) once said she had not been called to her profession by God, "but by one thing I feel very strongly about: the fight against impunity."
In that respect, Del Ponte, who also long served as Swiss attorney general, will face an uphill struggle as part of the United Nations Commission of Inquiry into rights violations in Syria.
The commission, headed by Brazilian Paulo Sergio Pinheiro and created a year ago, has conducted more than 1,000 interviews with perpetrators and victims in the spiralling conflict in a bid to document atrocities so the guilty can later be held accountable.
In a report published last month, the commission, which so far has been barred from entering Syria to see the situation on the ground, accused the regime and to a lesser extent rebel forces there of committing war crimes and crimes against humanity.
When it comes to demanding accountability and pushing for access for UN investigators, Del Ponte, with her shortly cropped blond hair and unrepentant, no-nonsense attitude, might very well be the right person for the job.
The Sicilian Mafia and their Russian counterparts, Swiss bankers, Serbian ethnic cleansers and Rwandan genocidaires: Del Ponte has tracked them all.
But her endeavours have come at a price and her forthright style has earned her more high-profile enemies than almost anyone else in public life.
Born in the Ticino Italian-speaking region in southern Switzerland, she started her career as a district attorney in her home canton where the Mafia are known to have salted money away in Swiss secret bank accounts.
She earned her tough reputation for fighting drugs and arms trafficking and international money laundering as Switzerland's state attorney from 1994 to 1999, before moving on to head the ICTY and the ICTR in 1999.
In 2003, she was pushed out of the Rwandan court — where she had been charged with investigating the genocide in which up to one million mainly Tutsi Rwandans died in 1994 — after the government of President Paul Kagame has refused to cooperate with the investigation, and sought her removal.
It was probably no coincidence that her problems with the Rwandan authorities began when she announced in typically abrasive fashion that she intended to investigate members of the Tutsi-led armed forces for atrocities they may have committed when they invaded Rwanda in the wake of the genocide.
But she remained a thorn in the side of Serbian nationalists until 2008, when she resigned from the ICTY.
Perhaps her most famous challenge was the attempt to bring former Yugoslav president Slobodan Milosevic to justice, facing charges of crimes against humanity, but he died in his cell in 2006, just a few months before his verdict in The Hague was due.
Even after Milosevic's arrest, Del Ponte repeatedly accused Serbian authorities of doing nothing to apprehend the two men alleged to be his principal henchmen, Ratko Mladic and Radovan Karadzic.
They were both eventually caught, but only after Del Ponte had left the Hague-based court.
Del Ponte was also part of the drugs investigation that eventually sent the brother of former Mexican president Carlos Salinas to jail.
In 1988 she came to the attention of the Sicilian Cosa Nostra and only narrowly escaped assassination together with her mentor, Italian investigator Giovanni Falcone, who was killed in a later Mafia ambush.
Her detractors dismiss the twice-divorced Del Ponte's methods as high-handed — but few deny she gets results.
"The Mafia dislike me, but they're not the only ones," she once commented.
"Some Swiss bankers find me a little bit over-zealous as well."
Del Ponte retired in 2011 and lives today in Ticino, where she grew up.
It was the Swiss government that proposed last month that she take part in the UN Syria probe.
"Referring to such a strong and well-known personality gives a clear message that justice is coming for the Syrian criminals," a Western diplomat at the UN in Geneva told AFP on Friday.