The history that makes up Fitzrovia Hospital dates back to the opening of the original St Luke's Hospital in 1892.

St Luke's Hospital for the Clergy was a charity founded in 1892 to support sick members of the Anglican clergy and which owned a hospital in Fitzroy Square, London. The hospital project was founded in 1892 by Canon William Henry Cooper and his second wife and opened initially as a hostel in Beaumont Street. In 1904 two houses were acquired in Fitzroy Square. Each was rebuilt, the first being opened by Queen Alexandra in 1907, and the second opened by Queen Mary in 1923. The Queen Mother visited the hospital in 1957.

In 1994, the hospital was refurbished and redeveloped in a scheme designed by architect Ronald Wylde Associates. On 17 January 1995, it was rededicated by the Archbishop of Canterbury, and officially reopened by Queen Elizabeth II, accompanied by the Duke of Edinburgh, on 8 March 1995. St Luke's Hospital for the Clergy re-branded itself as St Luke's Healthcare for the Clergy in January 2010 and supported the physical and mental health of the Anglican clergy from Church House in Westminster.

The hospital underwent a complete refurbishment in 2006 - 2007 at a cost of £3 million pounds which included a new patient trolley lift, operating theatre and systems whilst undergoing a full internal refurbishment. Now under new management, further improvements are underway which started back in 2021 in order to redecorate the building, upgrade the operating suite to include laminar flow, the creation of a teaching faculty with new lecture theatre plus clinical research facility including clinical trials unit and laboratories.