Around 125 firefighters are tackling a blaze at Somerset House in central London.
Videos posted on social media show grey smoke billowing into the air from the landmark building, over the River Thames and nearby Waterloo Bridge.
The director of Somerset House Trust said the fire broke out in the west wing of the building and there are "no artworks in that area".
There are no reported injuries and the cause of the fire, which was first reported around midday, is not yet known.
London Fire Brigade (LFB) said the entire site at Somerset House has been closed to the public whilst the blaze is dealt with.
Posting on X, Somerset House wrote: "Owing to a fire in one small part of Somerset House, the site is currently closed.
"London Battle and other events today will not take place. We apologise for any inconvenience."
Staff and visitors to the gallery are standing outside and clouds of grey smoke can be seen several streets away.
Due to heavy smoke, the London Ambulance Service has asked people to avoid the area and told local businesses to keep windows and doors shut.
Somerset House is on the Strand in central London and is currently used as an arts venue. The Georgian era buildings and square were built on the site of a palace dating back to the Tudors.
The venue is also home to the Courtauld Gallery, an art museum which houses the collection of the Samuel Courtauld Trust, including masterpieces ranging from the Middle Ages to the 20th century.
Vincent Van Gogh's Self-Portrait with Bandaged Ear is listed as a part of the Courtauld collection.
The gallery also houses works by Edouard Manet, Claude Monet and Paul Cezanne.
Somerset House regularly hosts exhibitions, experiences and ice skating within its famous courtyard.
Director of Somerset House Trust Jonathan Reekie said the site was "immediately evacuated" when the fire was spotted in the "west wing" area.
"Everybody is safe, there are no valuable artefacts or artworks in that part of the building," Mr Reekie told the OceanNewsUK.
"For now we just want to let the London Fire Brigade get on and do their brilliant work."
LFB said its crews are tackling flames which are "located in part of the buildings roof".
Twenty fire engines including crews from Soho, Islington and surrounding fire stations are at the scene, the Brigade added.
Two of the Brigade's 32m (104ft) ladders have been sent to the scene as part of the operation to tackle the blaze.
"Traffic in the surrounding area will be impacted as crews respond," LFB said in a statement.
The Met Police said officers were called at 12:25 and attended along with LFB firefighters.
Road closures are in place, the force said adding nobody is thought to be inside Somerset House.
