The fire broke out at Lavalla Catholic College junior campus in Grey Street, Traralgon, about 1.30am Saturday, the Country Fire Authority (CFA) said.
Eight fire trucks were called to the scene and it took firefighters 45 minutes to bring the blaze under control.
The fire destroyed five classrooms and an office in the arts/graphics centre at the school.
"The teenagers are assisting police with their enquiries regarding the fire at Lavalla Secondary College this morning," Senior Constable Cassy Stone said.
"Both of the teenagers are 15-year-old boys; one is from Traralgon and one is from Tyers."
Fire investigators estimate the damage bill to be more than $100,000.
There were no injuries sustained as a result of the fire.
Two teenagers arrested over school fire (The Age, 12/8/07)
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Lavalla Catholic College