St Ann’s was consecrated in July 1712. Before the 18th century, Manchester had only one church, now the Cathedral. As the town grew, Lady Ann Bland funded a new one. St Ann's was likely designed by John Barker in the classical style, using the purplish-red sandstone from nearby Collyhurst. 

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From 1887 – 89 the interior was remodelled by Alfred Waterhouse, architect of the Town Hall. He raised up the chancel, created the vestries and Lady Chapel and moved the pulpit to one side. At the West End the stairs and gallery were also changed. The original Communion Table, the gift of Lady Ann Bland, was put into the new Lady Chapel. 

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The Descent from the Cross, painted in the style of Annibale Carracci (1561) hangs behind the font at St Ann's. The painting was bought from Italy by a Churchwarden of St Peter’s, it hung in St Peter's until it was demolished in 1907. In a very different style altogether is the art deco window. It is in memory of Hilda Collens who founded the Northern School of Music in 1920. This School is now part of the Royal Northern College of Music whose students perform regularly in St Ann’s.

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The organ, which dates from 1730, has grown over the years and is now a fine instrument with 54 speaking stops on which recitals are given every week. It was rebuilt by George Sixsmith & Co of Mossley in 1996.

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​St Ann’s narrowly escaped damage during the Manchester WW2 air raids by the Luftwaffe and still has a burnt-out incendiary bomb which fell onto the roof. In 1996 an IRA bomb devastated Manchester city centre and caused the upstairs windows of St Ann's to be blown in one side and out on the other. Fortunately the organ had been removed for rebuilding and so was preserved