The center was established in 1917 as the Davao Public Hospital. It was a 25 bed capacity hospital in San Pedro St., Davao City. In 1946, the hospital was renamed as the Davao General Hospital increasing its capacity to 200 beds. In 1957, the hospital transferred to its current location at JP Laurel Avenue, Bajada Davao City. It was renamed Davao Regional Medical and Training Center by virtue of the Republic Act. 1859. In 1966, the hospital was transferred to the 12.8 hectare site. Because of its importance in health care delivery the Department of Health issued Administrative Order 157 designating it as the medical Center for Mindanao and Sulu. During the martial law years and the conflict between the MNLF/MILF/NPA and the government of the Republic of the Philippines, the hospital was the major trauma center.
In 1986, the Davao Mental Hospital, which previously was an extension of the National Center for Mental Health was transferred to the hospital. At that time, the hospital was renamed the Davao Medical Center and the bed capacity was increased to 600. The name Davao Regional Hospital and Training Center was then transferred to the then Davao del Norte Provincial Hospital. The hospital, then under the supervision of Gerardo Cunanan, MD, completed a renovation of the facilities and upgraded the number of operating theaters. In 2007, The Mindanao Heart Center was established.
On November 2009, RA 9792 was enacted, changing the name of the Davao Medical Center to Southern Philippines Medical Center and increasing its bed capacity from 600 to 1,200, thereby upgrading its service facilities and increasing its medical personnel.