The southern part is a continuation of John Street, off Theobalds Road. The northern part crosses Guilford Street and terminates in Mecklenburgh Square.

Once known as Upper John Street, this thoroughfare runs from Mecklenburgh Square to Henry Street. It was developed over thirty years beginning in 1792 by Henry Doughty of Bedford Row when the Foundling Hospital extended Guilford Street east over his land. Doughty Street now consists of (mainly grade II listed) Georgian houses which were built between 1790 and the 1840s. Many of the houses have been converted into legal offices though in the last few years, many have been converted back to family homes.

In the nineteenth century, Doughty Street was an exclusively residential and had portered gates at either end to restrict entry.

One notable resident was Charles Dickens. On 25 March 1837, Dickens moved with his family into number 48 on which he had a three-year lease at £80 a year.

He remained here until December 1839 and wrote Oliver Twist in the house. In 1925, the Dickens Fellowship acquired his former house at No. 48, saving it from demolition and opening it as a museum. Other buildings were destroyed in the Second World War but reconstructed resembling their original style. With its gates and distinguished residents, Upper John Street remained an elegant enclave through changing times.

Other notable residents included clergyman and editor Josiah Pratt at No. 22 from 1797; chemist Edward Charles Howard, who discovered mercury fulminate around 1799-1802 at his laboratory at No. 6; witty author Sydney Smith at No. 8/14 from 1803; architect William Brooks, whose son Charles was born at No. 52 in 1816 and became Punch editor; Alfred Ainger, architect of the first University College Hospital, whose son Alfred was born at No. 10 in 1837.

Other mid-century residents were builder Thomas Cubitt at No. 53 and Daily Telegraph founder J.M. Levy at No. 51. In 1869, poet Charlotte Mew was born at No. 30/10 where her father was an architect's assistant. No. 46 later housed health campaigner Edith Summerskill's childhood home.

The London Post Office Railway passes underneath the street, but is now disused.