One wrote: "Absolutely devastating ~my heart goes out to those students ~ just unbelievable to have happened again".
At least 20 fire engines are on site and witnesses said flames were licking 50ft into the air within minutes of it starting.
Speaking as she visited the scene, First Minister Nicola Sturgeon said:"It's heartbreaking".
"The Glasgow School of Art was a home away from home for 4 years and still such an important part of my life".
"It's hard really to say much until there's an evaluation or report on the building".
A file photo of the school's Mackintosh building.
By morning, the Grade-A listed structure could be seen gutted against the morning sun, with stone pillars and destroyed timber framing among the only remaining elements of the iconic, pioneering Arts and Crafts-style structure designed by Charles Rennie Mackintosh in 1896.
Buildings including the O2 ABC have suffered "extensive damage" as flames and smoke poured into the night sky from the Glasgow School of Art building which has been undergoing a multi-million pound restoration project.
A number of roads around the art school were closed while crews tackle the blaze.
The 2014 fire, begun when gases from a foam canister used in a student project were ignited accidentally, caused significant damage and restoration work was still underway.
Writing on Twitter, Paul Sweeney, a Glasgow MP, said: "It looks like the entire interior space is now fully alight".
The Mackintosh building was completed in 1909 based on designs by Charles Rennie Mackintosh, Scotland's most-lauded designer.
He said the government "stands ready to help, financially or otherwise".
In recent years, the school has produced numerous UK's leading contemporary artists such as Douglas Gordon, Alison Watt, David Shrigley, and three recent Turner Prize winners: Simon Starling in 2005, Richard Wright in 2009 and Martin Boyce in 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.
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