The school is named after St Ambrose Barlow, one of the Forty Martyrs of England and Wales.

Building work commenced on Ash Wednesday 1953 and the school entered use in January 1955 with the official opening and blessing on 16 February 1955, by Bishop Henry Vincent Marshall.

[4] At another inspection carried out by Ofsted in 2018, the school was rated as "requires improvement" Another Ofsted inspection was carried out in March 2022, the school was rated as “requires improvement” Executive Principal, Mrs. C. M. Garside, was awarded CBE for Services to Education in January 2015.

The old site of St Ambrose Barlow was used for filming the CBBC show 4 O'Clock Club for both interior and exterior shots.

The former site was used as the set of Waterloo Road, from January 2023 until February 2024, from Series 14 onwards the school will move to the former Nicholls Campus of The Manchester College as Waterloo Road joined the trust and relocated to a new premises.