Saint Agatha School officially opened on September 22, 1941, welcoming its first class of 42 first-grade students. It was initially located at the former Bowditch Estate at 336 Adams Street, on what is now Father Carney Drive, which served as both a school and a convent. Sister Savina, CSJ, served as the school's first principal. St. Agatha Parish itself had been established earlier in June 1922 under founding pastor Father Carney, growing to serve families across Milton and Quincy.

Under the leadership of Monsignor Daniel J. Donovan, construction began for a new, permanent school building. The modern school building at 440 Adams Street was completed in 1951, where it remains today. As the new building neared completion, a parishioner donated a statue of Our Lady of Fatima. Though an initial request to rename the school after Our Lady of Fatima was denied by the Archbishop to avoid confusion with the parish name, the statue was placed in front of the school, where it still stands.

Religious sisters guided the academic and spiritual life of the school for over 60 years. A member of the Sisters of St. Joseph served continuously as principal from the school's founding in 1941 until the retirement of Sister Roberta Ristuccia, CSJ, in 2002. Over the decades, other religious communities—including the Sisters of Charity of Halifax and the Sisters of Notre Dame de Namur—also contributed significantly to the parish and school's music, outreach, and religious education programs.

Today, Saint Agatha School operates as an accredited member of the New England Association of Schools and Colleges (NEASC), serving nearly 430 students from Preschool/Early Childhood through Grade 8 hailing from Milton and more than 20 neighboring communities.