Fire broke out in the Brazilian landmark, which houses over 20 million artefacts, at 7.30pm local time.
The building is surrounded by firefighters, though they don’t yet have the blaze under control.
It is not believed that there have been any casualties.
President of Brazil Michel Temer said: “It is incalculable for Brazil to lose the collection of the National Museum.
“It is a sad day for all Brazilians.”
From photos it is clear that fire engulfed the entire building.
Stunned onlookers looked on as the blaze spread across the museum.
Fire swiftly speed across the entire building.
The cause of the fire is currently unknown.
Firefighters have reportedly been warning local residents that the museum could collapse.
Rescue workers and museum staff desperately attempted to save what they could from the historic collection.
It includes the oldest fossil ever found in Brazil as well as ancient Egyptian, Roman and Greek artefacts.
The site also contains a major scientific library holding nearly 500,000 items, including 2,400 rare works.
The museum, which is tied to the Rio de Janeiro federal university and the education ministry, was founded in 1818.
Shocking photos show firefighters desperately trying to contain the blaze.
According to local media they are trying to stop the fire reaching a part of the museum which contains chemicals.
Alexander Kellner, the museum’s famed director, is on the scene assisting.
The Museu Nacional was one of the largest museums of human and natural history in the Americas.
It was installed in the Paco de Sao Cristovao, formerly the home of the Brazilian Imperial Family.
The building was turned into a museum in 1892, and has been listed by Brazilian National Heritage since 1938.