The school has been undergoing renovations since the previous fire in May 2014.
About 50 crew remained at the scene almost 12 hours later, working to extinguish "a few pockets of fire", the fire service said.
"(The fire) reached from the ground floor right through to the roof.
Scottish First Minister Nicola Sturgeon tweeted: 'Thoughts with you GSofA - I know [firefighters] will be doing everything they can'.
A huge fire devastated a historic building in Glasgow, Scotland, overnight.
"But it is hard to find words to convey the utter devastation felt here and around the world for the iconic Mackintosh building", she wrote.
"The fire, as I think everybody could see from the pictures last night, has been a devastating blaze, much much worse than the one that took hold of the Mackintosh building four years ago so the damage is severe and extensive".
Police Scotland advised the public to avoid the area, and said areas around Dalhousie St, Scott St and Sauchiehall St were all affected by road closures.
"It is just a shell", she said.
The blaze which tore through the Mackintosh Building in 2014 began when a projector ignited gases from expanding foam used in a student project.
"The best we can probably hope for is structural facade retention and a complete rebuild of the interior".
The Scottish First Minister stated: "Once again, we are indebted to the bravery of our firefighters and other emergency services".
The fire at the building, which was designed by artist and architect Charles Rennie Mackintosh and built between 1897 and 1909, has been called "devastating" by the city council leader Susan Aitken. "The UK Government stands ready to help, financially or otherwise", he said in a statement.
In recent years, the school has produced numerous UK's leading contemporary artists such as Douglas Gordon, David Shrigley, and three recent Turner Prize winners: Simon Starling in 2005, Richard Wright in 2009 and Martin Boyce in 2011.
"The 2014 fire destroyed around 20 percent of the western wing of the building".