Msgr. Henry Brann opened the Saint Agnes parish elementary school on East 44th Street in 1892. The Sisters of Charity initially staffed the school. Because of growing enrollment, in 1904 the Marist Brothers educated the upper classes of boys. In 1923, Msgr. John Chadwick added high school classes for boys under the direction of the Marist Brothers. By the 1950's, the residential neighborhood was developed into business offices, and the parish elementary enrollment dwindled. In 1962, the elementary grades were eliminated and the entire school building was renovated to accommodate an expanded high school that drew students from all parts of the city.
Commercial development in the parish continued, and in 1989, the school moved to temporary quarters on East 33rd Street to allow the sale of the former school building adjacent to the parish church.
In 1992, the school moved to its present site on West End Avenue in the Upper West Side of Manhattan. The first year in the new location also marked the hundredth anniversary of service to young people in the City of New York.
On September 1st, 2009, St. Agnes Boys High School was incorporated as a New York State Educational Corporation and established a Board of Directors to govern the school.