Smoke poured into the night sky as the flames took hold of the building which has been undergoing a multi-million pound restoration project.
Crews were called to the scene at around 11:20pm with the fire spreading "in the space of a few minutes".
No casualties have been reported following the fire, the Scottish Fire and Rescue Service said.
Local resident John McInnes, 22, said: "I can't believe that this has happened again to such an iconic building. It's unbelievable.
"Questions need to be asked, they spent so much on renovation, but this seems so much worse than the last one."
Former Glasgow School of Art student Peter Swanton, who also witnessed the 2014 fire, described his devastation at seeing the building in flames again.
The designer wrote on Twitter: "The Glasgow School of Art was a home away from home for four years and still such an important part of my life. To see this from my roof hurts."
Another witness Connor Neil said people were being evacuated from their homes and there was a "big orange light” which could be seen from across the city centre.
The 22-year-old chef from Glasgow said: "We've got just to the top of Renfrew Street and police closed off the road.
"You can just see a big orange light coming from the school and people are being evacuated from their homes."
Fire took hold of the Glasgow School of Art building in May 2014 in the run-up to the students' degree show, and graduation ceremonies had taken place at the institution earlier on Friday.
A restoration project, which was set to cost between £20 million and £35 million, had been returning the famous art school to its former glory, with Brad Pitt and Peter Capaldi among those lending their support.
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.
Paul Sweeney, shadow Scotland minister, said the Mackintosh Building was the “most architecturally important building” in the city.
He added: “Oh dear, the 1909 library extension, that was the origin of the 2014 blaze is now fully alight too. It looks like the entire interior space is now fully alight.
“The best we can probably hope for is structural facade retention and a complete rebuild of the interior. Devastating.”
Scottish First Minister Nicola Sturgeon said she was heartbroken by the fire and paid tribute to the emergency services.
She tweeted: “This is clearly an extremely serious situation. My first thoughts tonight are for the safety of people – but my heart also breaks for Glasgow’s beloved @GSofA.
“Once again, we are indebted to the bravery of our firefighters and other emergency services.”
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