The school was founded by charter of Philip and Mary in 1555. The oldest sections of the school were built in 1567, formerly referred to as the "big school" and is now used as the school library. South End Site became the model for Boston Latin School which was the first school in what was to become the United States of America. The school still retains the Latin motto 'Floreat Bostona' (May Boston Flourish). This motto also forms the title of the official school song, written by Dr G.E. Pattenden, headmaster from 1850–1887, which he referred to as 'my school hymn'. The song is still sung at official school occasions such as Prizegiving, Charter Day and Beastmart.
In the 1960s when under Holland County Council Education Committee, it was a voluntary controlled school with around 500 boys, 550 by the 1970s, and 600 by the 1990s. The school had a CCF.
In recent years girls have been admitted to the sixth form for the first time. There were 597 pupils on the roll as at April 2008, including 170 in the sixth form. The school has been awarded Technology College and Sports specialist status. In December 2012, Boston Grammar School shut its doors for the final time as a selective school, run by the local authority. In January 2013, Boston Grammar School re-opened as a selective academy.
On 1 January 2013, Boston Grammar School became a converter academy, under the leadership of the then headteacher, Mr Paul Marsh. No changes were made to the school uniform and the school retained its existing name. This ended the federation between Boston Grammar School and Boston High School, with both schools now having an independent governing body, budget and establishment number.
In 2006, there were controversial plans by Lincolnshire County Council to federate Boston Grammar School with the local girls grammar school Boston High School, with effect from September 2011. In 2010 it was announced that due to the withdrawal of Building Schools for the Future funding by the new coalition government, that both schools would operate as two separate schools, still under a federation - on two sites - with one governing body. This arrangement ended when Boston Grammar School became an Academy in 2013.