A church was established on this site, at the centre of the old walled city, in Anglo Saxon times; records of 1086 note the church as previously belonging to an estate held by Aubrey de Coucy, likely Iffley, and the parish including part of Littlemore.
In the early days of Oxford University, the church was adopted as the first building of the university, congregation met there from at least 1252, and by the early 13th century it was the seat of university government and was used for lectures and the award of degrees. Around 1320 a two storey building was added to the north side of the chancel — the ground floor (now the Vaults cafe) became the "convocation" house used by university parliament, and the upper storey housed books bequeathed by Thomas Cobham, Bishop of Worcester, which formed the first university library.
When Adam de Brome became rector in 1320 the church's fortune became linked to what would later become Oriel College. In 1324 de Brome founded St Mary Hall and appropriated the church's rectory house, including small tithes, oblations, and burial dues for the college, an act confirmed in 1326 by the bishop, Henry Burghersh, after de Brome had King Edward II's patronage to refound the college. De Brome diverted the revenue of the church to his college, which thereafter was responsible for appointing the vicar and providing four chaplains to celebrate the daily services in the church. Early provosts of the college were inducted into their stall in the church, and until 1642 fellows were required to attend services on Sundays and holy days