All nearby properties were evacuated.
Ironically, restoration after a less severe 2014 fire was just being completed when this new inferno began.
Officials said Saturday morning the fire was not completely out but was under control, and latest television footage showed firefighters continuing to spray jets of water at the building to try and prevent further damage.
He said it was likely that all the restoration work carried out since the last fire had been destroyed.
Scotland's first minister, Nicola Sturgeon, said her government would "do anything we reasonably can" to ensure the building's future, but added: "Obviously all of us hope the building can be saved but I think it's too early to draw conclusions".More news: Morocco to bid for 2030 World Cup after losing 2026 bid
"The Glasgow School of Art was a home away from home for 4 years and still such an important part of my life".
Witnesses said the blaze took over the building in a matter of "minutes".
The rear elevation of the Glasgow School of Art is seen on fire, in Glasgow, Scotland, Britain, June 15, 2018, in this still image obtained from social media.
"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.
"There will be disruption around Dalhousie Street, Sauchiehall Street and Renfrew Street and I would advise the public to avoid these areas at this present time".
Eyewitnesses told the BBC that the fire looked "much worse" than the last one.More news: Donald Trump confident of 'terrific relationship' with Kim Jong Un
The landmark building had been due to reopen next year after restoration.
First Minister of Scotland commended the "bravery" of firefighters and emergency services as they battle the flames.
This is one of Glasgow's most treasured buildings, built between 1897 and 1909.
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 global icon of art nouveau architecture.
The school's alumni include recent Turner Prize for art winners Simon Starling (2005), Richard Wright (2009) and Martin Boyce (2011).More news: Kane expects 'brave' and 'aggressive' England in Russian Federation