Staff at the Boys Model School in north Belfast arrived on Monday morning to find the main building covered in graffiti alleging that pupils were involved in pushing drugs, and threatening reprisals.
Headteacher Jim Keith said the staff were "shattered", but no parents had threatened to remove their children from the school, which has more than 1,000 pupils.
One graffito read: "This school enrolls drug dealers as young as 14. Parents, do you know where your child is?"
It is the second time the school in Ballysillin has been targeted by loyalist factions, and follows claims that a list of alleged drug dealers, including pupils' names, was circulating in the area.
It is comparatively rare for schools in the province to become caught up with paramilitary activity.
Mr Keith said: "Drugs are a problem in this community and this neighbourhood but I can say with confidence that this is a drug-free school.
"We have not had a single drug-related incident in the school, which is why we are shattered that this has happened.
"We have been operating during the entire 25 years of the troubles but all the problems that that could entail are left at school gates.
"We have been a haven of order and calm in the midst of a very bad situation. I am concerned that this could affect the reputation of the school but hopefully that will not happen.
"So far all the parents have been supportive and the pupils are more excited by all the media attention than the graffiti."
The Model School also has a rolling programme of education about drugs and other substances, which involves outside agencies.
Mr Keith said he had seen a list of names and believed there was "something sinister" behind the graffiti attack.
Ulster Unionist councillor Fred Rogers said there was a growing frustration about the drugs problem, and he had contacted paramilitaries to try to defuse the situation. "The school has done as much as it can to stamp out the problem, and there is an agreement in this area that there will be no punishment beatings here," he said.
Since last summer, five people have been shot dead by an organisation calling itself Direct Action Against Drugs, widely seen as a cover name for the IRA.
And last week the loyalist Ulster Volunteer Force ordered 15 people to leave Northern Ireland under a threat of death for alleged drugs involvement.
But because the killings and related assaults and threats have occurred within communities, rather than across the sectarian divide, the Government has chosen not to regard them as an immediate risk to the peace process.