President Emmanuel Macron of France was among the first to react to the shocking scenes, as the iconic building caught fire Monday night.
Barack and Michelle Obama shared messages on both Twitter and Instagram, respectively, to share their personal memories of the Cathedral and say that "we're thinking of the people of France in your time of grief."
Michelle Obama recalled the "majesty of Notre Dame" taking her "breath away" the first time she was there, as "a teenager on a school trip to Paris."
"So being here in Paris tonight, my heart aches with the people of France," she wrote. "Yet I know that the Notre Dame I experienced all those years ago, as so many others have over the centuries, will soon awe us again."
Hillary Clinton echoed those sentiments, posting on Twitter that her "heart goes out to Paris" and that the cathedral remains a "symbol of our ability as human beings to united for a higher purpose."
Queen Elizabeth II sent a personal message to President Macron seen by ABC News, in which she said, "Prince Philip and I have been deeply saddened to see the images of the fire which has engulfed Notre-Dame Cathedral."
"I extend my sincere admiration to the emergency services who have risked their lives to try to save this important national monument," she wrote. "My thoughts and prayers are with those who worship at the Cathedral and all of France at this difficult time."
Pope Francis was said to be praying for "all those who are striving to cope with this tragic situation," according to the Director of the Vatican Press Office, Alessandro Gisotti, who described Notre Dame as "a symbol of Christianity in France and in the world."
President Donald Trump, meanwhile, provoked considerable bemusement on social media by suggesting Monday "flying water tankers" could be used to put the fire out.
He later posted another tweet saying, "God bless the people of France!"
After initially reacting to the shocking images, most of the messages from world leaders proclaimed this was a time to come together in the aftermath of a great tragedy. President Macron posted on Twitter Monday night it was "part of our French destiny" to rebuild to cathedral "all together."
The leaders of Germany, the United Kingdom and other world powers also expressed their condolences to the people of France, as did a number of religious leaders, such as the Archbishop of Canterbury, Justin Welby.
"Tonight we pray for the firefighters tackling the tragic #NotreDame fire - and for everyone in France and beyond who watches and weeps for this beautiful, sacred place where millions have met with Jesus Christ," Welby posted on Twitter. "Nous sommes avec vous."
But it was the video of bystanders singing "Ave Maria" as the cathedral was engulfed in flames that arguably had the biggest impact worldwide.
The video originally posted on Twitter by France-based journalist Ignacio Gil has been viewed over 12 million times.