The Chapel is the only remaining building of the 13th Century Hospital of Saint Mark. The Hospital was founded by Maurice de Gaunt in 1220 as a daughter house of Saint Augustine's Abbey, now Bristol Cathedral. In 1230, Robert de Gournay, nephew and heir of Maurice de Gaunt, reformed the Hospital into a fully independent religious community, with a Master, four Chaplains and eight Clerks and twelve poor Scholars.
The first Master was Henry de Gaunt, the brother of Maurice and uncle of Robert de Gournay. The function of the Hospital was to provide food and care for one hundred poor people per day. The Hospital and its work continued for over three hundred years until the dissolution of the monasteries in 1539. The Hospital and its lands were purchased by the City Council, who granted the use of the hospital buildings and its grounds to the newly founded Queen Elizabeth Hospital School for Boys. The Chapel was appointed as the place of worship for the boys and later for the girls of the Red Maids School, founded on land nearby in 1621.
In 1732 the Bristol Grammar School, founded in 1532, exchanged buildings with Queen Elizabeth's Hospital and remained here until their new premises were built at Tyndall's Park in 1877. In 1885 the Society of Merchant Venturers established a School and Technical College on the site of the old Hospital buildings.
In 1687 the Chapel was granted as a place of worship for French Huguenots who had settled in Bristol after being forced to flee persecution in France when the Edict of Nantes was revoked. They continued to use the chapel until 1722 when they moved to a new building in Orchard Street.
In 1722 the City Council, who until that time had worshipped in the Cathedral, decided to make the Chapel their official place of worship following a dispute with the Catherdral over seating. They continue to use the Chapel to this very day. In 1788 the Mayor of the time invited John Wesley to preach in the Chapel after the Bishop of Bristol had refused him permission to preach in any of the city's churches.