And by seeking arrest warrants for Israel Prime Minister Benjamin Netanyahu and senior Hamas figures, Khan has shown he is not afraid to take on the world's most controversial cases.
The application followed an arrest warrant issued last year for President Vladimir Putin of Russia, which promptly slapped arrest warrants on Khan himself.
But then the 54-year-old Briton has faced down controversy throughout a career that has included stints defending Liberia's former president Charles Taylor against allegations of war crimes in Sierra Leone.
Other high-profile clients have included Kenya's President William Ruto in a crimes-against-humanity case at the ICC that was eventually dropped, and the son of late Libyan leader Moamer Kadhafi, Seif al-Islam.
Asked about "crossing the floor" -- working as both prosecutor and defence -- Khan told specialist publication OpinioJuris that it helps lawyers stay "grounded."
It also prevents "corrosive traits such as thinking that defence counsel is the devil incarnate or that as a prosecutor you are doing 'God's work'," he said.
Criticised initially for not acting fast enough to prevent atrocities in Gaza, Khan touched off a firestorm when applying for arrest warrants on Monday.
Netanyahu called it a "moral outrage of historic proportions", fellow accused Defence Minister Yoav Gallant lashed it as "despicable." For US President Joe Biden, it was "outrageous."
Even before Khan's application, senior US Republicans penned a letter threatening to bar him and his family from the United States, ending ominously "you have been warned."
But Khan has held firm, telling CNN: "We are not going to be swayed by the different types of threats, some of which are public and some of which may be not."
"This is not a witch hunt. This is not some kind of emotional reaction to noise... It's a forensic process that is expected of us as international prosecutors."
'Guilty as charged'
Born in Scotland, Khan was educated at the private Silcoates School in northern England, before studying undergraduate law at King's College, London.
His father was Pakistani, his mother British and he is a member of the minority Ahmadiyya Muslim sect, sometimes sprinkling his speeches with "inshallah" (God Willing).
Called to the bar in 1992, he went on to cut his teeth in international law at the former Yugoslav and Rwandan war crimes courts from 1997 to 2000.
He later represented survivors and relatives of victims of the 1970s Khmer Rouge regime in Cambodia at its UN-backed court in the late 2000s.
His other roles have included a stint at The Hague-based Special Tribunal for Lebanon, set up to bring to justice the killers of Lebanese ex-PM Rafic Hariri in 2005.
More recently, he headed the UN special probe into Islamic State group crimes and called for trials like those at Nuremberg of Nazi leaders.
Initially absent from a list of candidates for the top ICC prosecutor job, Khan was added reportedly at the insistence of the Kenyan government.
The ICC selection panel described him as a "charismatic and articulate communicator who is well aware of his achievements."
"I don't think it was a compliment," Khan quipped to OpinioJuris.
"I did apply because I thought I could do the role. If the Search Committee thought this was arrogance, then I'm guilty as charged," he said.
In his speeches, he is forthright with a strong command of oratory, sprinkled with dashes of British humour.
"From what I've observed, Karim Khan seems like a no-nonsense lawyer, which I quite respect," Melanie O'Brien, visiting professor in international law at the University of Minnesota, told AFP.
An ICC prosecutor "has to have a certain fortitude because you know that you are going to be up against people who don't agree with you and don't agree with the court generally," she added.
Driving Khan appears to be a thirst to deliver justice for all, regardless of outside influence.
"It's very dangerous to succumb to popular demand -- it's very important to follow the evidence," he told AFP in a 2022 interview.
And the stakes, he believes, could hardly be higher.
"If we don't apply the law equally, we're going to disintegrate as a species," he told CNN.
