Our Lady of Lourdes High School was founded in April 1958 by Francis Cardinal Spellman, who purchased the former Poughkeepsie High School building and grounds from the Poughkeepsie Board of Education. The school was given its name in honor of the centenary of the apparition of the Virgin Mary at Lourdes in France. The new school opened its doors in September 1958 with a faculty of four brothers and four sisters, and an athletic coach. The original school was divided into two halves, one for the boys and one for the girls. Opening enrollment was 280 students. The boys' school opened with four classes of 35 students each, as did the girls' school. Our Lady of Lourdes existed this way as separate schools until 1967.
The campus moved to a suburban location on Boardman Road in the Town of Poughkeepsie starting in the 1996-1997 school year at the location of the former IBM Homestead.
The school was led by Father John Lagiovane from 2007-2014. The 2014-2015 school year began under the leadership of the new principal, Catherine Merryman, in September 2014.
Our Lady of Lourdes is a member of the New York State Public High School Athletic Association.