Smoke and flames billowed from the Glasgow School of Art as firefighters rushed to tackle the blaze which began at around 11:20 pm (2220 GMT) on Friday.
There were no casualties, the fire service said.
First Minister Nicola Sturgeon said her heart “breaks for Glasgow’s beloved” art school, which is housed in one of Scotland’s most cherished buildings.
“This is clearly an extremely serious situation,” she said.
Local residents were being evacuated from their homes with the glow from the blaze visible across the city centre, witnesses told Press Association.
The news agency said the fire had spread to a nearby campus and a nightclub.
The fire broke out four years after another blaze tore through the art school in May 2014, badly damaging the building which was designed by architect Charles Rennie Mackintosh.
This fire ‘much worse’
Eyewitnesses told the BBC 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” with firefighters facing “an extremely challenging and complex incident”.
Writing on Twitter, Paul Sweeney, a Glasgow MP, said he was “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.”
Mackintosh, a Glasgow-born architect and designer (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. It 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. —AFP