The station was part of the world's first underground railway, the Metropolitan Railway, which opened between "Bishop's Road" (now Paddington) on the Hammersmith & City line and "Farringdon Street" (close to the present-day Farringdon station). It was opened on 10 January 1863 as "Portland Road", renamed "Great Portland Street and Regents Park" in 1923 and changed to its present name on 1 March 1917.
The current structure was built in 1930 on a traffic island on the Marylebone Road at its intersection with Great Portland Street and Albany Street. Its construction is a steel framed cream terracotta clad exterior, with the perimeter providing shops and originally a car showroom with office space over the station. Great Portland Street was at a major sales location for the motor industry. It was designed by the architect C.W. Fowler and Grade II listed in January 1987.
The station is across the street from the main building of International Student House, a student residence and hostel and is also near Harley Street medical district, famous for its doctors and surgeons.