The land in which Monsignor Bonner and Archbishop Prendergast High School is located was originally owned by Christopher Fallon, who built a mansion on the site in 1850. In 1882, the mansion was bought by Colonel Anthony J. Drexel. The mansion was situated on what was then called the "hill of Drexel", which led to the area becoming known as Drexel Hill. In 1908, the mansion burned to the ground with only the gatehouse, which had served as servants' quarters, remaining.
In 1917, the Archdiocese of Philadelphia purchased the 33 acres (130,000 m2) for $57,000. Archbishop Edmond Francis Prendergast subsequently announced the construction of St. Vincent's Orphanage, which was to be operated by the Sisters of Charity of the Blessed Virgin Mary. Work on the project was slowed by the war, and Archbishop Prendergast died before the work was completed.
On May 9, 1920, the dedication of the new orphanage took place and was attended by Archbishop Dennis Dougherty and Pennsylvania governor William Cameron Sproul.
St. Vincent's functioned as an orphanage for over 30 years. By 1952, the number of children needing care had dwindled, and Archbishop John Francis O'Hara decided to move the remaining orphans to a smaller building in St. Davids and convert the facility into the new Archbishop Prendergast High School, an all-boys' school, which opened in 1953. The facility was turned into a high school to seek to meet the increasing demand for a Catholic high school in the expanding western suburbs of Philadelphia. In 1956, the archdiocese opened a new building on the same tract and named it Monsignor Bonner High School in honor of Monsignor John J. Bonner, a former superintendent of schools for the archdiocese. With the new construction, Monsignor Bonner then became an all-boys' school, and Archbishop Prendergast became an all-girls' school.
In 2005, the archdiocese's Office of Catholic Education announced that Monsignor Bonner High School and Archbishop Prendergast High School would unite in a co-institutional model with one administration. The new administration would include a single president, principal and assistant principals overseeing both schools. The new model became official for the 2006–07 school year.
In January 2012, as part of the wider 2012 Archdiocese of Philadelphia school closings, Archbishop Charles J. Chaput announced that both Monsignor Bonner and Archbishop Prendergast would close at the end of the school year at the recommendation of a blue ribbon commission. The basis of the commission's recommendation was founded upon the real estate value of the school land and their potential income after possible retail development. Soon after the announcement was made, the school administration began the appeal process which outlined plans for the improvement of both schools. In a 13-day span, alumni and supporters donated $1.11 million to keep the school open. Additionally, just days before the final decision regarding the schools was to be made, a group of business people came forward to help not just the two schools, but other high schools slated to close as well. On February 24, 2012, Archbishop Chaput announced that the schools would remain open, though they would now fully merge into one co-ed school known as Monsignor Bonner and Archbishop Prendergast High School. To accommodate the merger, the girls would move out of the Archbishop Prendergast building and into the Monsignor Bonner building beginning with the 2012–13 school year.