All nearby properties were evacuated.
A restoration project had been returning the famous art school to its former glory, with Brad Pitt and Peter Capaldi among those lending their support.
Stuart Robertson, director of the Charles Rennie Mackintosh Society, said the 2014 fire was contained before damaging the east wing of the building but that this blaze had damaged its entire structure.
There were no casualties, the fire service said. "My first thoughts tonight are for the safety of people - but my heart also breaks for Glasgow's beloved @GSofA".
It has been described as "a working art school as well as a work of art", and has an A-list rating from Historic Scotland.
Aiden continued to film the fire for approximately 30 minutes, commenting that despite the fire crews best efforts to fight the blaze, the fire only seemed to grow.
Alan Dunlop, professor of architecture at te Glasgow School told The Guardian, "The building does look as though from the inside it's been totally gutted".
All of the school's buildings will remain closed for the next week.
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Fire has caused "extensive" damage at Glasgow's famed Mackintosh Building and hit multimillion-pound restoration work carried out in the aftermath of a previous blaze, a fire officer has confirmed.
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.
Mackintosh's building, which was so unpopular upon construction that its designer wasn't invited to the opening ceremony, became a symbol of the innovative and distinctive Glasgow Style-an worldwide icon of art nouveau architecture.
"The Mack has been undergoing restoration since the last devastating fire in 2014".
Charles Rennie Mackintosh, one of Scotland's most influential figures, inspired designers, architects and artists around Europe with his distinctive style.
"This is clearly an extremely complex and large-scale incident, and one that is ongoing", she said.
The Scottish First Minister stated: "Once again, we are indebted to the bravery of our firefighters and other emergency services".
Massive fire at the Art School.