An eyewitness said the fire appeared to have started in the basement of the Charles Rennie Mackintosh building in Renfrew Street just before 12:30.
Smoke is billowing from the main windows, which are cracking, and through the attic studios.
Smoke is also drifting across the M8. Police have cordoned off Renfrew Street.
Four fire appliances are at the scene.
Six fire appliances were at the scene, with firefighters seen pouring water on the building from a high ladder as flames blew windows out.
Broadcaster Muriel Gray, a former student and current chairwoman of the school, arrived and burst into tears when she saw the building in flames.
A post on Twitter from the School of Art said: "The Mackintosh building is on fire, all have been evacuated & we will post updates as we get them. Currently setting up an incident number."
Austin Yuill, who works as a chef at the art school, told the BBC: "I've been moved two streets away from the Mackintosh building but before we left the place was completely ablaze all down the west side of the building.
"I'm told it started in the basement and it's worked its way all the way up through the five floors.
"As far as I know it started from a spark which has gone on to foam, expanding foam."
Asked how busy the art school was, he said: "It would be very busy because we're working up to the end-of-year assessments, so all the students were installing their work today all over the Mackintosh building. There are a lot of very upset students here."
He added: "Quite apart from it being voted the best building of the last 175 years, it is a major tourist draw and has an incredible reputation as an art school. This is really terrible."
The building is considered to be one of Scotland's most admired and influential buildings and Mackintosh is lauded as the country's greatest architect.
Mackintosh was a 28-year-old junior draughtsman at a Glasgow architecture firm when he drew up the designs for the building that many consider his masterpiece.
The dramatic art nouveau design took 12 years to be completed, opening in 1909, but it signalled the birth of a new style in 20th Century European architecture.
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