More than 500 sixth-form pupils at Methodist College in Belfast (MCB) are to be sent home and taught online for the rest of the school term.
The school took the decision after 35 positive cases of coronavirus among sixth-form pupils this week.
More than 300 pupils were identified as close contacts and 11 members of staff are also self-isolating.
The school is one of Northern Ireland's biggest with almost 1,800 pupils in 2019, including 535 in sixth form.
Term at Methodist College is due to end on Friday 18 December for all remaining pupils.
'Protecting college community'
In a letter parents on Friday, MCB's principal Scott Naismith explained the decision to tell sixth formers to stay at home.
"This week alone we have had 36 cases (and counting) amongst the pupils, 35 of them in sixth form," he said.
"A thorough contact tracing exercise is being carried out, which to date has identified over 300 pupils as close contacts who are required to self-isolate for two weeks.
"In addition, we have 11 members of staff who are self-isolating.
"I am in ongoing contact with the Public Health Agency and the Education Authority to keep them informed about this spike in cases and to take advice on our management of the situation.
"After full and careful consideration of all the information available, and in order to provide the sixth form with a meaningful learning experience and to protect the health and wellbeing of the college community, it has been decided that the sixth form should remain at home and be taught online for the remainder of this term.
"All other year groups should attend as normal."
'Exceptionally challenging situation'
Mr Naismith said that would allow teachers to focus on providing "high quality" remote lessons for sixth form pupils.
"Staff will maintain online contact with their pupils and make every effort to ensure that this time is used as productively as possible to minimize any impact on the pupils' A-level studies," he said.
"We wanted to be able to keep all of the pupils in school until 18 December and this is not the end of term that any of us would have wanted.
"But we are faced with an exceptionally challenging situation at the end of a very demanding term, and I have to act in the best interests of the pupils and the staff."
Mr Naismith asked parents to make sure their children complied with Covid-19 safety measures to "ensure that we can all have a healthy and safe Christmas to celebrate".
A deep clean of the school is also due to take place on Saturday and Sunday.
The Education Minister Peter Weir has recently said that schools would not close early for the Christmas break.
However, BBC News NI understands that Mr Weir is considering whether further changes to summer exams in 2021 are necessary.
That comes after a number of extra measures were introduced for GCSE and A-level exams in England.