The hotel was originally one of London's Victorian era railway hotels, the Great Central Hotel. It was first proposed by Sir Edward Watkin of the Great Central Railway who envisaged Marylebone station, which the hotel was to serve, as the hub of an international railway which would run through a channel tunnel. Sir Edward's aspirations proved to be overambitious (not for the only time as he was behind the Watkins' Tower, which was a failed attempt to outdo the Eiffel Tower), and after the Great Central ran into financial difficulties the site of the hotel was sold to Sir John Blundell Maple of the furniture company Maples, who opened his hotel in 1899. Marylebone station is one of the smallest of the central London termini, but its hotel was among the grandest of the London railway hotels. It had a clock tower and was built around a large central courtyard. There were two main entrances, one on the northern side facing the station and the other on the southern side towards Marylebone Road. The architect was Colonel Sir Robert William Edis and the style was eclectic and opulent. The Ladies' Alpine Club rented rooms in the hotel and held its annual dinner there.
In the 1920s the central courtyard became a winter garden, but the building's first period as a hotel was drawing to a close. With railway traffic falling due to the advent of the motor car, London's railway hotels were among the most vulnerable of the city's grand hotels as they were not in the most fashionable districts. The Great Central fell out of hotel use for over forty years. It was a convalescent home during the Second World War and served as a military office building for many years afterwards as well as the headquarters of the British Railways Board, and was referred to by railway staff as "The Kremlin".
In a pattern which was followed by several of the railway hotels it later returned to its original use, as demand for luxury hotels in London grew and the city centre expanded in the late 20th and early 21st centuries. The building was purchased by a Japanese company in 1986 and reopened as a hotel in 1993, under the name of The Regent, London. In 1995, it was purchased by the Lancaster Landmark Hotel Company Limited, and renamed The Landmark London. The Landmark Group is a Thai company which opened a hotel called The Landmark in 1987 and owns several other hotels in London. The hotel now has 300 rooms and suites.