Originally founded as Christian Brothers College, St Kilda (CBC St Kilda), and run by the Christian Brothers, the school has long since had a lay teaching and administrative staff; becoming co-educational as St Mary's College in 2021 following the closure of Presentation College Windsor (PCW).

In 1872, the parish priest of St Mary's Parish, Dr James Corbett wrote to the Presentation Sisters and Christian Brothers, calling for their assistance in providing Catholic education in the precinct, following the passing of the Educational Act of 1872 and the establishment of a nearby state school.

[3] In 2019, following the announcement of Presentation College Windsor's closure at the end of 2020, CBC St Kilda announced it would reregister from a single-sex boys school to a co-educational school that would operate across both sites.

[4] On 2 October 2023, the college announced that the lease on Presentation Campus (owned by the Presentation Sisters) will be terminated in September 2024 to allow more funding to be dedicated to capital works on the Edmund Rice Campus without having to raise tuition fees.

These capital works were constructed from November 2023, and up to the closure of Presentation Campus in September 2024.

[5] St Mary's College offers its senior (years 10–12) students the following pathways: * Does not allow for study scores or an ATAR to be calculated.