Holy Cross College in Strabane announced the closure on Wednesday morning.
On Sunday, the school said two members of the school community had tested positive for coronavirus. A deep clean was undertaken in response.
On Wednesday, the school, which educates around 1,550 boys and girls, said a further two cases had been confirmed.
In a Facebook post, the college said: “Unfortunately the school has had to close at very short notice this morning due to two further confirmed cases in the school community.”