The school building has one (possibly two) classroom. Miss Luna usually teaches in one, but it is possible that there is a second room where Mrs. Dotter teaches her own class. The school building also has an auditorium, seen in Judge Mia's Thanksgiving and Judge Mia Forever. It also has a party room (seen in Judge Mia's Halloween and Judge Mia's Valentine's Day. The building itself is a tall, apartment-like structure with at least six levels.
In Night of the Living Ape, the preschool is invaded by Turdsley and Buck, who are both zombies. Miss Luna is attacked, and the students rapidly transform into zombies until the whole school is infested. They are somehow cured after the episode.
During the Attack of the Children of Brownfeather in Brownfeather's Prophecy, PS-22 was off-screen, but events during the attack have been mentioned. There was a shooting by an unknown Child of Brownfeather, who wanted the cheese crackers in the closet. Matilda, and supposedly the other parents, took their children out of the school for safety. The school later recovered.