The original liberty of the area around East Smithfield was Liber Trinitae, where the Saxon King Edgar was petitioned by 13 knights, desiring to form a guild, to grant them the wasteland to the East of the city wall.

The strip of land given to the north of Aldgate came to be known as Portsoken, an extramural ward of the City of London. The open ground south of Aldgate was known as East Smithfield. Later, Edward the Confessor confirmed the liberties upon the heirs, and these were again confirmed in the reign of William II. By 1115, during the reign of Henry I, the entire soke, or liberty, was given to the church of Holy Trinity within Aldgate, which had been founded in 1107 by Matilda, Henry’s Queen.

The southern part of East Smithfield was given by Holy Trinity Priory as a site for the Hospital of St Katharine, founded by Matilda (wife of Stephen of England), in 1148. Further foundations were bestowed by Eleanor (widow of Henry III) and Philippa (wife of Edward III). The importance of the hospital was such that the whole of East Smithfield came to be deemed within the Precinct of St Katharine. A Pentecost fair was granted in the district in 1229, and by 1236 Jews were settled here for protection by the Tower garrison — until their expulsion in 1290.

Between 1347–1351, the Black Death struck the City. Two cemeteries were opened in East Smithfield to take the dead from London.

In 1442, the neighbourhood was constituted "a Precinct free from jurisdiction civil or ecclesiastical, except that of the Lord Chancellor". With the Dissolution of the Monasteries by King Henry VIII in 1531, the land became the property of the Crown, and many of the religious houses were given to prominent nobles.

With trade in the City regulated by the City, St Katharine became an area for foreign settlement. Foreign ships were not permitted to use the wharfs within the City, and St Katharine’s Quay came to be used extensively for unloading these, particularly Dutch ships. Many French settled here, after the loss of Calais. A large number were from the districts of Hammes and Guisnes, leading to a part of the area becoming known as Hangman’s Gains.

By the 17th century, the rights, peculiarities and administration of the Liberty was becoming increasing anachronistic, and in 1686, they were subsumed into the Liberties of the Tower of London.

By the end of the 19th century, the quay was the terminus for passenger boats arriving from northern Europe, and became the arrival point for Ashkenazi Jews fleeing persecution in eastern Europe. Many settled around Whitechapel and Spitalfields, half–mile to the north.

The Royal Mint moved from the Tower of London, to a site at the end of East Smithfield in 1809. In November 1975, the London Mint was closed and production transferred to Wales.

In 1828, St Katharine Docks were constructed on the site of the hospital, and some 11,000 persons were evicted from the slum. From 1855, the whole area of the former East Smithfield came under the administration of the Whitechapel District.