Beechworth Secondary College principal Patricia Broom said the destruction was discovered when staff arrived at school early on Monday.
"[I feel] frustrated by the incredible waste of money, time and energy - all for a stupid act of vandalism," Ms Broom said.
"It's a bit heartless."
Ms Broom said because the school was in the middle of a building program, it was not easy to find somewhere else for the displaced students to study.
"It's quite inconvenient, but we will work out a way to cater for the Year 12s and hopefully get it repaired in a hurry," she said.
A string of 'senseless' and destructive crimes targeting Beechworth Secondary College has caused tens of thousands of dollars in damage and seen a building condemned.
Detective Leading Senior Constable Ian Deverell said since January, the school has been the victim of several burglaries and instances of graffiti, culminating in the theft of a $70,000 excavator and destruction of a wall.
Overnight Friday offenders stole an excavator from a construction site at the school, drove it a short distances to the Year 12 building and used the excavator bucket to break a hole in the wall.
Detective Leading Senior Constable Deverell said the incident caused at least $50,000 of damage to the school while the excavator will need repairs worth about $500.
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"At this stage the building is going to be condemned until inspected by building inspectors," he said.
"These offences are senseless crimes.
"To have a community school like Beechworth Secondary College damaged the way it is, impacts the community and society, it costs money to taxpayers to repair the building and year 12 students at the school now have no building to utilise - it's disappointing."
Detective Leading Senior Constable Deverell stopped short of saying whether police suspect the same offenders are responsible for all attacks on the school, but said it was an unusual offence.
"Whether the school has been targeted by the same person, I can't say," he said.
"It's unusual for a small quiet town like Beechworth to be targeted on so many occasions in a short period of time."
Previously, desktop computers have been stolen from the school, but Detective Leading Senior Constable Deverell said it appeared nothing had been taken during the latest incident.
"It appears to be an act of vandalism, [with] no respect for the school," he said.
"We're currently viewing CCTV footage from the area and we're appealing to anyone who may have information in relation to this offence to contact detectives (02 6049 2600) or Crimestoppers (1800 333 000)"