Holy Ghost Preparatory School was founded in 1897 as a preparatory school and junior college seminary for young men who were studying to become members of the religious congregation of the Holy Ghost Fathers and Brothers. At that time, the school was called Holy Ghost Apostolic College and educated seminarians from first-year high school through second year college.

In the late 1950's, the Holy Ghost Fathers undertook a major revamping of their educational program. At this time, all the first and second year college seminarians were moved from Holy Ghost and sent to Duquesne University in Pittsburgh.

For the first time in its history, the school would open its doors to a high school student who was interested in preparing himself for college without entering the seminary program. It was at this time that the name became Holy Ghost Preparatory School. In 1968, the Holy Ghost Fathers discontinued the seminary program so that, at present, the entire enrollment of Holy Ghost Prep consists of non-resident, college-bound students.

The campus presently consists of four buildings: Cornwells Hall, constructed in phases between 1897 and 1923, is the oldest building on campus which houses the science laboratories, a computer center, classrooms, the McShain Art Studio, administrative offices and the Chapel of the Seven Gifts of the Holy Spirit; the Fieldhouse, built in 1962, is home to the athletic program; Spiritan Hall, built in the 1980's, was renovated in 2001 and is now offices for the President, Vice President, Director of Finance, Associate Director of Development, and the Director of Alumni & Annual Giving. ; and Founder's Hall, completed in the fall of 1999, a state-of-the-art facility which houses the Sonnenberg-Keeble library, classrooms, and the Abramson Family Computer Center.