The blaze engulfed the Glasgow School of Arts and spread to neighbouring buildings.
The fire spread to nearby buildings, including the O2 ABC music venue - although firefighters managed to prevent it taking hold any further.
Efforts to bring the fire under control are expected to be "prolonged", Deputy Chief Officer Iain Bushell said.
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 fire was first reported at about 20 minutes before midnight on Friday, when the city center was full of people enjoying a night out, including many School of Art students celebrating their graduation which took place earlier.
More than 60 firefighters are fighting the fire at the Mackintosh Building in Glasgow. Massive fire at the Art School.
Witnesses said the heat from the blaze could be felt a few streets away.
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There were reports that responders were unable to enter the school to fight the blaze from within for fear of structural collapse as the fire reached temperatures exceeding 1000 degrees Celsius, or over 1800 degrees Fahrenheit, temperatures almost hot enough to melt steel.
He added: "Oh dear, the 1909 library extension, that was the origin of the 2014 blaze is now fully alight too".
Nicola Sturgeon said the Scottish government stood "ready to provide any support" in the wake of the blaze.
"It is just a shell", she said.
Paying tribute to the fire service and other emergency services, the first minister added: "This is a very sad morning in the city of Glasgow".
Glasgow-born architect and designer Mackintosh (1868-1928) was a leading exponent of Art Nouveau, whose distinctive lines and lettering remain influential.
Secretary of State for Scotland David Mundell tweeted that he had been to see the restoration work only two weeks ago and that his "heart goes out to all those who had worked so hard on it".
Many deplored what they called the cruel irony of the fire coming hours after a giant mural depicting Charles Rennie Mackintosh was unveiled elsewhere in Glasgow.