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 1920s, 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 1950s, 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.

In the 1990s, the school began a long-range planning process, which resulted in significant structural enhancements to the campus.  A 400-meter all weather track and field event complex was built, surrounding a new soccer field. An additional baseball field was added and the existing field was redone. Founders' Hall, containing a new library, classrooms, and computer labs, was built to enhance the educational opportunities for all students. The entire Firebird Fieldhouse was renovated in 2003, including a new maple hardwood floor, new locker and bathroom facilities, a new weight and fitness center, and full climate control.

Holy Ghost Prep continues to evolve. In August 2017, the Brennan Family Innovation Center opened its doors. It has become a space that bustles with activity and innovation. All Holy Ghost Prep ninth graders take the Introduction to Engineering Design class in the center. In those classes, the students actively participate in the engineering process: identify, brainstorm, develop, build, and redesign. In addition, Holy Ghost Prep’s VEX robotics team collaborates in this space, and electric circuit classes are also taught in the Brennan Family Innovation Center. 

The Brennan Family Innovation Center marked the first phase of the two-phase project that result in a STEM Tower in the Northeast wing on Cornwells Hall. During the summer of 2018, the school’s biology, chemistry, and physics laboratories were transformed into STEM-based labs and combine with the Innovation Center in a STEM Tower that will make HGP one of the area’s leaders in science and technology education as these state-of-the-art spaces will allow Holy Ghost Prep to expand and develop its curriculum and eventually partner with area colleges to tackle real-world problems.

In March 2018, Holy Ghost Prep opened the Holt Center, the school’s new 27,000-square foot performing arts, athletic, and activity space. 

The Holt Center is having a major impact on the performing arts and athletic programs at Holy Ghost Prep. The building is home to the Di Paolo Family Gymnasium, a practice gym with six basketball hoops; the Frank Frederico ’00 Performing Arts Theater, a state-of-the-art performing arts space for school plays and concerts; music rehearsal spaces specifically tailored to accommodate both group and individual instruction; an erg room for the HGP rowing program; indoor batting cages and pitching mounds; and track and field practice space so HGP athletes can sharpen their skills all year round.