Smoke billowed from the top of the cathedral as flames ripped through its roof and bell towers.
It was not immediately clear what had caused the fire, while local media reported that police in the city were treating it as an accident.
The cathedral, which dates back to the 12th century and is famous for featuring in Victor Hugos classic novel "The Hunchback of Notre-Dame," attracts millions of tourists every year.
A major operation was under way, the fire department said, while a city hall spokesman said on Twitter that the area was being cleared.
President Donald Trump, meanwhile, addressed the fire in a tweet early Monday afternoon.
Notre-Dame was in the midst of renovations, with some sections under scaffolding, while bronze statues were removed last week for works.
In a tweet the mayor of Paris confirmed the fire and called for called for people to remain away from the scene.
This story is developing. Please check back for updates.
--Reuters contributed to this report.