The hospital opened in 1902 as a 64 bed workhouse for poor sick people. By 1911 there were 520 beds.
During the First World War, the facilities were used as an army hospital. The facilities reverted to a workhouse in the early 1920s and were then greatly extended to accommodate all the sick. In 1924, the Southmead Infirmary was built and was later renamed Southmead Hospital. The hospital has been greatly expanded and now covers 60 acres (24 ha).
Records relating to hospitals within the Southmead Health Authority are held at Bristol Archives (Ref. 39880).
In 2005, a major expansion was planned which included moving most services from Frenchay Hospital to the Southmead site, with Frenchay being downgraded to a Community Hospital. The project was finished in late 2013 and opened in April 2014.
Full approval for the project was given by the NHS South West board in January 2009. In 2009, it was announced that Carillion was to design and build a new building, at a cost of £430 million, bringing all departments and services under one roof. Called the Brunel building, after Bristol engineer Isambard Kingdom Brunel, it has 800 beds, 24 theatres, patient gardens, a public square, a helipad and visitors' multi-storey car park.