This is the third building to be erected on this site. The original, elegant Palladian style Church of St Andrew was designed by G.D. Coleman and built in 1935-36. The second Church of St Andrew was designed by James Turnbull Thomson and built in 1842. It had a tower and spire but they were not architecturally very satisfactory and, as if in recognition of this fact, were twice struck by lightning, in 1845 and 1849. The whole building was condemned in 1852 and demolished in 1855.

The new building lacks the fine details of its early 13th century English prototype said to be the Netley Abbey in Hampshire, UK, due largely to the fact that it was built by Indian convicts, as were many buildings of the day. Nevertheless, Lieutenant-Colonel Ronald MacPherson's (Executive Engineer) design for the church (which was consecrated as a cathedral in 1870) has some good qualities and makes a prominent contribution to the Padang and Singapore's skyline.

MacPherson is remembered in the grey and red granite memorial monument surmounted by a Maltese cross in the grounds and by the stained glass window over the big west door. Jalan Klapa was renamed MacPherson Road in remembrance of his work.

The Right Reverend Daniel Wilson, Lord Bishop of Calcutta, laid the foundation stone on 4 March 1856, and the 1st service was held on 1 October 1861. The Right Reverend G.E.L. Cotton, who succeeded Daniel Wilson, had the honour of consecrating the Cathedral on 25 January 1862. In 1869, it was transferred from the jurisdiction of Calcutta to the Diocese of Labuan and Sarawak and, in 1870, Archdeacon John Alleyne Beckles consecrated it as the Cathedral Church of the United Dioces

The grounds of the Cathedral include some fine examples of Adenanthera pavonina (Saga tree).

St. Andrew's Cathedral is owned by the Synod of the Diocese of Singapore and was gazetted as a National Monument on 28 June 1973.