The street is named after Margaret Bentinck, Duchess of Portland, daughter of the local landowner Edward Harley, 2nd Earl of Oxford and Earl Mortimer.

[3][4] William Winlaw was an 18th-century engine-maker who was based in Margaret Street.

All Saints Church, a Victorian Grade I listed Anglo-Catholic church, designed by the architect William Butterfield and built between 1850 and 1859, is located on the north side of the street.

[5] Audley House is a grade II listed block of flats built in 1907, at 9–12 Margaret Street on the corner with Great Titchfield Street.

The London Fo Guang Shan Temple, established in 1992, is located at 84 Margaret Street.