"To see Notre Dame in flames breaks my heart", one person tweeted.
Outside of animations, the iconic structure can be spotted in movies such as Is Paris Burning? and Berlin Express.
"It's been 800 years that the Cathedral watches over Paris", Pascal said". Hundreds of people lined up bridges around the island that houses the cathedral, watching in shock as acrid smoke rose in plumes.
Notre Dame has become a regular feature in Hollywood films - but it was perhaps best popularised by Quasimodo, the monument's fictional deformed bell-ringer.
French President Emmanuel Macron has arrived at Notre Dame.
"Notre-Dame is perhaps one of the most lovely buildings I have ever set foot in, and watching it burn down is absolutely soul crushing", read one Twitter post. The fire appears to have started in the roof where work is taking place.
Vice President Mike Pence offered his "thoughts and prayers" to the people of Paris, as he talked about the "heartbreaking" sight of seeing a holy site on fire. "Like all our compatriots, I am sad this evening to see this part of us burn".
The 1996 Disney film, The Hunchback of Notre Dame, was based on the 1831 novel of the same name, and follows Quasimodo as he struggles to gain acceptance in society.
Later, while in Minnesota for a speech on the economy, Trump called the fire "one of the true catastrophes" and said "the television images he'd watched during his flight were "a bad sight to behold".
"There will be nothing left", a cathedral spokesman told media.
Paris Mayor Anne Hidalgo sent out a message to residents of the city via Twitter: "A awful fire is underway at Notre-Dame Cathedral in Paris". He suggested the use of "flying water tankers" on the fragile 12th-century structure and warned France "must act quickly!"
View from the top of the Paris' Notre Dame Cathedral with the Eiffel Tower in background as the religious statues descend to earth for the first time in over a century as part of a restoration, in Paris Thursday, April 11, 2019.
As well as the home church for thousands of local Catholics who attend regular services, the cathedral is a huge attraction in the City of Lights, with tourists coming from across the world to see the building's historic architecture and artifacts.
The cause of the blaze was not known. The spire was undergoing renovation.
He also commented on reports the fire was caused by ongoing renovations.
Police in the capital said there were no deaths so far and the origin of the fire was unknown.