In mid 1980s, the National Guard Health Affairs (NGHA) initiated a number of postgraduate programs in various medical fields and subspecialties. NGHA advanced medical facilities at King Abdulaziz Medical Cities in Riyadh, Jeddah and Al Ahsa have contributed to the success of these programs, and paved the way for the university’s inception in 2005.

KSAU-HS's headquarter is in Riyadh, but it has two additional campuses in Jeddah and Al Ahsa. Riyadh Campus hosts six colleges: College of Medicine, College of Dentistry, College of Pharmacy, College of Public Health and Health Informatics, College of Applied Medical Sciences, and College of Nursing. Jeddah Campus hosts two colleges; College of Medicine and College of Nursing. Al Ahsa Campus hosts two colleges; College of Applied Medical Sciences and College of Nursing.

Being under the umbrella of NGHA has given the university and its students access to King Abdulaziz Medical City in Riyadh, Jeddah and Al Ahsa; the most advanced medical complexes in the region. Furthermore, it has enabled the university to enhance its curricula and academic programs with clinical applications and training under the supervision of highly competent health professionals.