This is the fourth church to serve this parish. The first, circa 1200, dedicated to St John the Evangelist, was the parish church of Tyburn and stood in the vicinity of the present Marble Arch.

In 1400 it was demolished and a new church built nearer to the village of Marylebone. This was on the site of the memorial garden at the north end of Marylebone High Street. This church was dedicated to St Mary the Virgin, by the bourne; the Ty bourne being a stream running from what is now Regent's Park down to the Thames. In course of time the dedication became St Mary le burn, corrupted to St Marylebone. The great Elizabethan philosopher Francis Bacon (1561-1626) was married there in 1606. The interior of the church was accurately portrayed by the artist Hogarth (1697--1764) in the marriage scene from his famous series "The Rake's Progress" (1735).

The original of the pew panel depicted in that picture can be seen at the back of the church in the north west corner.