By 1185–86 Sydenham was a chapelry of the prebendary parish of Thame. In the English Reformation in 1547 the Act for the Dissolution of Collegiate Churches and Chantries dissolved all prebendaries, and the tithes of Sydenham passed to the Wenmanfamily. The earliest parts of the Church of England parish church of Saint Mary are Norman corbels in the walls of the chancel. However, in 1293 it was reported that the church was "in ruins" and a rebuilding had just begun. This was carried out in the Early English Gothic style.The church retains most of the lancet windows inserted during the rebuilding.
The timber-framed bell tower was built at the same time. It is one of a number of wooden bell-towers in SouthOxfordshire. The others include St Helen's, BerrickSalome, All Saints, Didcot; St Nicolas, RotherfieldGreys and St Mary the Virgin, Waterperry.
Early in the 14th century a Decorated Gothic east window was inserted in the chancel and a rood screen and rood loft were added. Late in the 15th century the nave was given a hammerbeam roof.The rood screen and loft were removedin 1840.In the chancel is a set of Medieval corbels that formerly supported a Lenten veil to screen the altar. Such veils were discontinued in the English Reformation, and these corbels are a rare survival.
Sherwood and Pevsner state that the architect John Billing restored St Mary's in 1856,but the Victoria County History states that the restoration was in 1877.By both accounts the tower was rebuilt, the chancel and nave lengthened and a vestry and south porch added. the Victoria County History adds that the tower and its arches were moved some distance to the west. The two lancet windows west of the south porch were added during the restoration, and the 14th-century style west window of the nave was probably added at the same time.
The church is a Grade II listed building. The parish is now part of a single benefice with the parishes of Aston Rowant, Chinnor and Crowell.