Originally, this school was located in downtown Guelph at the intersection of Cork and Norfolk Street, next to the Basilica of Our Lady Immaculate.

In 1953, the co-educational Notre Dame High School was erected, and at this time, laywomen and men joined the Sisters as part of the teaching staff.

In September 2004, the recommendation of the committee finally came forth as the existing school on Clair Road West opened, starting with grades 9 through 11.

Grade 12 has since been added, thereby enabling full granting status of the Ontario Secondary School Diploma, continuing the tradition of the Loretto Sisters and Celtic Pride in Guelph.

On June 16, 2009, Grade 9 student Isabel Warren was tragically killed by a cinderblock wall collapsing on her in a washroom facility in Larry Pearson Park, which is located behind the school.