The area was developed in the late 18th century by Henrietta Cavendish Holles and her husband Edward Harley, 2nd Earl of Oxford.

The area of Marylebone in which Weymouth Street is located originally belonged to the Manor of Tyburn which existed at the time of the Domesday Book (1086).

At the beginning of the 1900s, following lease expiries, large mansion blocks were developed near the main intersections of the street.

"[8] The street was lined with trees in 2010 as part of a neighbourhood community and stakeholder-based greening initiative.

[9] Notable residents who have lived on Weymouth Street include Edward Foley (1747–1803), MP, the second son of Lord Foley, of Foley House [10] Ernest Vaughan, 4th Earl of Lisburne (no 40), James Butler, 1st Marquess of Ormonde (no 14), the portraitist Mary Grace, the actress Mary Wells (actress) (no 12), Michael Faraday (no 18), the writer Jane Marcet (no 49), Queen Marie-Louise Coidavid of the Kingdom of Haiti - the first Black monarchy established in the Western world - (also no 49)[11] and psychoanalyst Dr Estelle Maud Cole, journalist and broadcaster Gilbert Harding, the entertainer Hughie Green and the pathologist Professor Keith Simpson (the latter four all lived at 1 Weymouth Street).