It is named after Cardinal Francis Spellman, the sixth archbishop of the Archdiocese of New York.

In September 1959, the newly created Cardinal Spellman High School opened in temporary quarters (formerly, the Biograph Motion Picture Studios of Thomas Alva Edison) on Marmion Avenue in the Tremont section of the Bronx.

Its permanent location on Baychester Avenue, between Boston Road and East 233rd Street in Edenwald, covers thirteen acres (including ball fields, grandstands, running track, and parking lots).

Many years later, the name of Needham Avenue, in front of the school, was officially changed by then Bronx Borough President and alumnus Fernando Ferrer to Cardinal Spellman Place.

At first the school was co-institutional, with separate classes for boys (staffed by diocesan priests, Brothers of the Christian Schools and laymen) and for girls (staffed by the Sisters of Charity of Mount St. Vincent and laywomen).