It is in the city's West End, facing Glossop Road and close to the main campus of University of Sheffield and the Collegiate Crescent campus of Sheffield Hallam University.

The hospital, which replaced both the Sheffield Royal Hospital and the Sheffield Royal Infirmary, was designed by Adams, Holden and Pearson and built in two phases; the first phase, a three-storey out-patients department was completed in 1971.

[2][3] The main building was designed as three main interlinked buildings, the most significant being the monolithic 21-storey concrete structure, which remains the third highest in Sheffield after St Paul's Tower and the Arts Tower.

[5] Operation of the hospital was transferred from the Sheffield Health Authority (dissolved on 1 April 1992) to the newly created Central Sheffield University Hospitals NHS Trust on 1 November 1991.

[6] The Jessop Wing, which replaced the Jessop Hospital for Women as a provider of maternity and gynecology services, was designed by the George Trew Dunn Partnership[1] and opened by the Earl of Scarbrough, Lord Lieutenant of South Yorkshire in 2001.