By Agence France-Presse
Smoke and flames billowed from the building, one of Scotland's most cherished, and firefighters rushed to the scene around 23:20 pm Friday. There were no casualties, the fire service said.
Scotland's First Minister Nicola Sturgeon said her heart "breaks for Glasgow's beloved" art school.
"This is clearly an extremely serious situation," she added.
Local residents were being evacuated from their homes with the glow from the blaze visible from across the city centre, witnesses told the Press Association.
The fire comes after a blaze tore through the art school in May 2014, badly damaging the building designed by architect Charles Rennie Mackintosh.
Eyewitnesses told the BBC that the fire looked "much worse" than the last one.
Iain Bushell, deputy chief officer for Scottish Fire and Rescue Service, told the broadcaster that efforts to bring the fire under control are expected to be "prolonged", and firefighters were facing "an extremely challenging and complex incident".
Paul Sweeney, a Glasgow MP, said on Twitter: "Devastated that a major fire has broken out at the Glasgow School of Art tonight.
"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."
Glasgow-born architect and designer Mackintosh (1868-1928) was a leading exponent of Art Nouveau, whose distinctive lines and lettering remain influential.
He won a competition to design the building in 1897 and it took around 10 years to complete but is now a landmark in the city, with special government-protected status.
The school's alumni include recent Turner Prize for art winners Simon Starling (2005), Richard Wright (2009) and Martin Boyce (2011).
Others include "Doctor Who" actor Peter Capaldi, Harry Potter and James Bond movie actor Robbie Coltrane, and members from the Scottish rock bands Travis and Franz Ferdinand.