The building served the large ancient parish of St Pancras, which stretched from a point a short distance north of Oxford Street, northward to Highgate.

A vicar of the church claimed (at some point prior to 1870) to have seen a document in the Vatican Library that placed the foundation to the 4th century, during the Roman period.

[10] Gillian Tindall has suggested that the lumps and bumps in the fields to the west of the church that Stukeley interpreted as a Roman camp were actually traces of the original medieval village of St Pancras, before the centre of the settlement moved north to the area now known as Kentish Town.

[13] Sharpe noted, when plotting his gridlines, that a number of ancient parish churches appeared to be on or close to intersections, or at least on road alignments.

In 597, Pope Gregory the Great sent Augustine of Canterbury at the head of a group of 40 monks intending to promote the re-establishment of Christianity in England.

J. Carter Rendell (vicar 1912–26) argued that a medieval altar slab marked with five consecration crosses, found during the 19th-century building works, could be dated to the 6th century.

Phil Emery and Pat Miller discuss the archaeological history of the site in 'Archaeological findings at the site of the St Pancras Burial Ground and its vicinity': The 1847 reconstruction of the medieval church revealed Roman tiles in the fabric of its tower and an inscribed altar stone dated to AD 625 (other sources estimate an AD 600 date[14]), which might suggest an early 7th-century foundation.

[15] In 1870 local historian Samuel Palmer reported "This old and venerable church is said to be the first Christian place of worship in the county of Middlesex in the eighth or ninth century.

The reasons for this were probably the vulnerability of the plain around the church to flooding (the River Fleet, which is now underground, runs through it) and the availability of better wells at Kentish Town, where there is less clay in the soil.

[18] After the Reformation the isolation and decay of the church made it a tempting resort for Catholics: indeed, it was said that the last bell which tolled for the Mass in England was at St Pancras.

[21] The church fell into disrepair and towards the end of the 18th century services were only held there on one Sunday each month; on other weeks, the same congregation would use a chapel in Kentish Town.

[24] There were further restorations in 1888 by Arthur Blomfield with the reredos by C E Buckeridge; in 1925 when the plaster ceiling and the side galleries were removed,[3] and in 1948 following Second World War bomb damage.

Charles Dickens mentions it by name in his 1859 novel A Tale of Two Cities, making it the location of body snatching to provide corpses for dissection at medical schools, a common practice at the time.

Burials in the churchyard eventually ceased under the Extramural Interment Act in 1854, and St Pancras and Islington Cemetery was opened in East Finchley.

[39] In the mid-1860s, the young Thomas Hardy was in charge of the excavation of part of the graveyard in the course of the construction of the Midland Railway's London terminus, St Pancras station.

[41] A recent addition is a polished marble stone at the entrance to the church, a collaboration between and a gift from the poet Jeremy Clarke and the sculptor Emily Young.

On 28 July 1968, The Beatles were photographed in the churchyard grounds, in a famous series of pictures designed to promote the single "Hey Jude" and the White Album.

[48] On 24 September 2014, singer Claudia Brücken, best known for her work with German electronic group Propaganda, performed a solo show at the church.