Holy Ghost Preparatory School was founded in 1897 as a preparatory and junior collegiate seminary for young men who were studying to become members of the Congregation of the Holy Spirit. At that time, the school was called Holy Ghost Apostolic College and educated seminarians from first-year high school through second-year college. Each student lived at the seminary in areas that today have been made into classrooms.

In the 1920's the name of the school was changed to Holy Ghost Missionary College, a reflection of the important Spiritan apostolate in the African missions that continues to this day.

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

The first group of day students entered in 1959 and attended class side by side with the high school seminarians. During the following years and as the school's population grew, its reputation for excellence became synonymous with its name. Improvements were made in both the physical plant and the educational and extracurricular programs. The construction of the gym (1962), the addition of new math, science and language programs, the expansion of the interscholastic sports program and non-athletic activities such as dramatics, newspaper, yearbook, and forensics have all served to further the school's aim of providing a well-rounded educational experience for each student. In 1968, the Spiritans discontinued the seminary program so that, at present, the entire enrollment of Holy Ghost Prep consists of nonresident, college-bound students.

In 1970, Holy Ghost Preparatory School was formed as a non-profit corporation. The Provincial Council of the Congregation of the Holy Spirit, U.S. Province-East, served as Board of Directors for the school until 1992, when a Board of Trustees was created by them. This Board consists of a minimum of eleven and a maximum of seventeen members, and is composed of Spiritans and lay men and women.

The cemetery is at the southeastern side of the grounds, behind Cornwells Hall near the rear of Spiritan Hall. It is surrounded by a large hedge.