In 1745, when the area was still open fields, Bonnie Prince Charlie led the last uprising in the Jacobite Rebellion in his bid for the crown. When in Manchester he used this area as a gun park, an event commemorated in the name Artillery Street and identified on a plaque on the wall of no. 15 Byrom Street.
A Georgian church, St John's, stood on the site of what is now St. John's Gardens. The churchyard contains the remains of a remarkable number of people associated with the rise of Manchester as a world industrial city. Over 22,000 are buried here, including William Marsden who originated the Saturday half-day holiday in 1843. The church was built in 1769 by Edward Byrom, a wealthy entrepreneur who also built the first quay on the River Irwell, giving rise to the name of the nearby Quay Street. It was demolished in 1931.
It is not known exactly when St John Street was laid out, but it takes its name from the church and it is reasonable to assume that the houses in the street were built as they were required, between 1770 and 1830. Not all the street was built up by then, as the 1850 map shows the site of no. 9 to be a timber yard. Early residents represented a broad mix of occupations, but with the passage of time occupancy became almost exclusively connected with the medical and legal professions. Consultants and specialists still comprise the majority of occupants in St John Street.
While the houses fronting the street were built for middle class and professional people, behind them were at least three back streets at right angles where workers lived in very small dwellings. They would have been workers in commerce rather than domestic staff from the larger houses. These smaller dwellings were poorly constructed and have long since disappeared. The sites they occupied have become gardens and courtyards to the surviving larger houses.
Richard Cobden (1804-1865), the politician and reformer, lived in the Georgian house on the corner of Quay Street and Byrom Street. It was later purchased under the will of John Owens, a wealthy textile merchant, and opened as Owens College in 1851. Later still it became the Victoria University of Manchester. From 1878 until 1990, the house was used as the County Court. John Owens, with his parents and brothers, was buried in St John's Churchyard.