The church stands on the site of an earlier one and incorporates its 15th-century medieval tower. On 9 April 1713 the ancient church's 14th-century nave collapsed. The painter Godfrey Kneller was a churchwarden of St Mary's at the time and was active in the plans for reconstruction in the Neo-classical style by the local architect John James. A local resident, Lady Wentworth, wrote a month after the collapse that it had been foreseen by a new vicar, Dr Pratt: Inside the 18th-century church some older monuments have survived from the medieval nave, including a brass to Richard Burton, the King's chief cook, and Agnes his wife, dated 1443. On 20 June 1721 Dr Pratt baptised at the church "James Shandayes and John Twogood", described as two Indian princes. They were followed in 1747 by Henry Fielding's son William. Hallam Tennyson, son of the poet Alfred, Lord Tennyson, and eventually second Governor-General of Australia, was christened at the church in 1852. The 18th-century nave of the church is in red brick with Tuscan pilasters and pediments. Following the reconstruction of 1713–14, the church was enlarged in 1754 and contains fittings of the same period, including a reredos and gallery fronts. The tower has a ring of eight bells, of which one dates from the early 16th century, three from the 17th and four from the 18th.
Extent of parish
Like the ancient church on the site, the present one began life as the parish church for the whole of Twickenham. However, housing development in the 19th and 20th centuries led to new parishes being created for several new Church of England churches: Holy Trinity, Twickenham Common, St Philip and St James Church, Whitton, St Stephen's, East Twickenham, All Saints, Twickenham and All Hallows, Twickenham. As these came into being, the parish of St Mary's became smaller, but it still takes in most of central Twickenham.
Sir William Berkeley, Governor of Virginia from 1660 to 1677, was laid to rest in the crypt of the church in 1677, unusually encased in "lead exactly fitted to the shape of the body, shewing the form of the features, hands, feet, and even nails", instead of a coffin. A year later he was joined by the remains of his brother Lord Berkeley, one of the Lords Proprietor of New Jersey. The brothers are commemorated in a memorial window in the present church, under which the ancient crypt survives.
Sir Godfrey Kneller died in 1723 and his remains were entombed in the church.
Alexander Pope lies in the church under a stone slab engraved simply with the letter P, near a bronze memorial plate, joining his mother, Edith Pope, who had been buried in the church in 1733.
The well-known actress and soprano singer Kitty Clive was buried in the churchyard in 1785. A plaque to her memory was affixed to the outside wall in the north-east angle of the church chancel.
There is a memorial to timber merchant James Montgomrey’s wife Henrietta in the church, but both she and her husband were buried at Isleworth Cemetery
The funeral of Neil Aspinall, head of The Beatles' company Apple Corps and sometimes called "the fifth Beatle", took place at the church in 2008, although Aspinall was buried at Teddington.
