St. Patrick's was established on May 6, 1861, and officially registered as a high school in 1867. Its founder was Rev. J.A. Willy of the Society of Jesus (the Jesuits), who controlled the school till June 1935. It was then taken over by the Franciscan order till 6 October 1950. Since 1950 it has had Pakistani principals belonging to the Roman Catholic Archdiocese of Karachi.
Stephen Raymond became the first Pakistani principal of his alma mater in 1950. The era of Fr. Raymond as principal from 1950 to 1974 is referred by old students as the 'golden era' of St. Patrick's. Fr. Raymond is credited with constructing the Cambridge Building (1950), St. Patrick's College (1952), the Teachers' Training College (1959), the first School Auditorium (1972). The school celebrated its Centenary in 1962 with the President of Pakistan, Field Marshal Mohammad Ayub Khan as the Chief Guest.
St. Patrick's High School was one of the few private educational institutes that escaped nationalization in 1972.
To commemorate the 125 years of the School, the Pakistan Post Office issued a special stamp in 1987.
On May 6, 2011, The former students of the school instituted the Father Stephen Raymond Gold Medal to be awarded to the top student from the Commerce Section, as part of the 150th anniversary of the school.