It was founded in 1882, when the city was part of British India, by Gregory De Groote, a Belgian Benedictine priest.

[1][2] The school, located on Municipal office street of Luxmibazar neighborhood of old Dhaka, was named after Pope Gregory I (540–604).

In 1882, the American priests of the Congregation of Holy Cross took over the Vicariate of East Bengal from the Benedictine Fathers.

Wise — who were Protestants — ran a school at present Wiseghat area near the River Buriganga.

[citation needed] In July 1923, Father Hennessy gained permission to change the European style school to the Education Board examination.

In the year of 2016, the school was upgraded to Higher Secondary level by Ministry of Education of Government of People's Republic of Bangladesh.

Pal Chaudhury, along with two of his teenage sons, Shoibal and Utpal who were students of St. Gregory's at the time, had been murdered.

Mr. Monoranjan Poddar, a student of Jagannath College and Mr. Sutradhar's brother-in-law had also been kidnapped by the Pakistani army from the school and was murdered on March 31, 1971.