The former British Army officer was the director of Mayday Rescue charity that trained members of the Syria Civil Defence or White Helmets, playing a major role in its creation in Turkey in 2013.
He was awarded an Order of the British Empire for his work three years later.
His death comes just days after he was accused of being a spy in a tweet by the Russian foreign ministry.
It is not known how Mr Le Mesurier died, but Turkish media reported he may have fallen from the balcony of his apartment in the Turkish city.
“We were informed by his family that he had died,” Raed al-Salah, the head of the White Helmets told The Independent.
“We read that the police found his body outside his home in Istanbul. But as of now, the police are investigating the case and have drawn no conclusions yet. We are waiting for the police report,” he added.
Mr Salah said the White Helmets community were “devastated” by the news.
“James is a close friend to us and to the Syrian people, he supported the White Helmets as founder and director of the Mayday Rescue organisation. We are devastated.”
A neighbour told Reuters he was found dead early on Monday near his home in central Istanbul’s Beyoglu district. A diplomat said the circumstances around his death were unclear.
Maria Zakharova, a Russian foreign ministry spokeswoman, attacked Mr Le Mesurier during a briefing in Moscow on Friday accusing him of being a “former agent of Britain’s MI6, who has been spotted all around the world”.
In the comments, which were shared on Twitter by the Russian foreign ministry’s account, she claimed he working as a spy in the Balkans, and the Middle East.
Russia is one of the closest allies of Syrian President Bashar al-Assad and has repeatedly denounced the White Helmets for allegedly supporting terrorist organisations, by “staging” airstrikes to frame Syrian regime or Russian forces.
In many parts of the war-torn country the White Helmets are the only first responders available to be able to help those wounded during government or Russian air and artillery strikes.
On Friday in the same briefing Ms Zakharova claimed the White Helmets “stage provocations… planned and carried out a series of ruthless fake chemical attacks.”