The hospital was built between 1973–78 and officially opened 15 June 1979. A new Emergency and Urgent Care centre was opened in 2010.
There were concerns about the hospital's long term prospects, leading to protests in 2010.
In September 2014 a new renal dialysis unit run by Fresenius Medical Care Renal Services Ltd was opened at the hospital, with a contract to run for at least 7 years.
As part of the reorganisation of acute services in Wales a 24/7 inpatient paediatric service will be provided at West Wales General Hospital from October 2014. Withybush will have a new 12-hour paediatric ambulatory care unit