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The hospital was founded in 1872.

The hospital was created in 1994.

In May 2004, the Avon Foundation Breast Center opened at San Francisco General.

In 2008, a proposition was passed that gave the hospital an $888 million bond to replace the building and ensure it met state seismic safety regulations and modernize it.

In 2015, Facebook founder and CEO, Mark Zuckerberg and his wife Priscilla Chan, donated $75 million to the hospital. The hospital's name was changed to the Priscilla and Mark Zuckerberg San Francisco General Hospital and Trauma Center following the donation. In 2016, the hospital's new building was completed.

The following events occurred for this hospital:

• 1850: San Francisco Granted a city Charter and creates a Board of Health; cholera strikes, temporary hospital set up.
• 1857: City and County opens its first permanent hospital in the former North Beach schoolhouse at Stockton and Francisco streets.
• 1864: “In the fall of 1864, Hugh Toland opened his new medical school, which in 1872 would become part of the University of California. The Medical School building was located on Stockton Street near Chestnut adjacent to the City and County Hospital ... In 1865, Toland was granted permission to use the hospital for clinical instruction.” 
• 1872: “On August 28, 1872, the New City-County Hospital on Potrero Street was opened ... it was described as a two-story, wooden frame building with a brick foundation...” 
• 1873: Agreement allows City and County Hospital to serve as the clinical facility for the University of California Medical School.
• 1906: “The Earthquake and Great Fire devastate the City in April 18, 1906 ... the Hospital with its wood frame structure anchored on the firm rock of Potrero Hill survived more or less intact, with minimal injury to inmates or staff.” 
• 1907: Children's ward and contagious pavilion open.
• 1908: Second plague epidemic strikes; hospital pronounced unfit for patient care when plague infested rats and fleas are found there; wooden buildings burned to the ground by city order and patients moved to the old Jockey Club Racetrack in the Ingleside district, where box stalls and grandstands are converted into a temporary hospital; “Mission Emergency” Hospital, one of the city owned network, operates out of a shack on the Potrero Ave site.
• 1915: New San Francisco General Hospital, landscaped, red brick, Italian Renaissance-style complex, dedicated during the city's celebration of the completion of the Panama Canal; motorized ambulances replace the horse-drawn vans.
• 1924: Psychiatric ward opens to treat acutely ill patients and reduce state hospital admissions.
• 1959: “In May 1959 in the first contract with the University of California was signed and amounted to 1% of the total hospital budget or $154,000 ... the value of teaching programs to a public hospital was emphasized by the university in their negotiations with the city...” 
• 1963: “...a modern medical library funded primarily by UC was opened on Ward 31. It was named the Briggs-Barnett library after two former chiefs of medicine on the UC and Stanford service.” 
• 1965: “The pressing need for more psychiatric beds, the general overcrowding, and the problems of maintenance and staffing all combined to emphasize the inadequacy of the 50-year-old hospital ... a $33.7 million bond issue ... passed overwhelmingly with the highest support of any bond since the earthquake of 1906.” 
  • 1971: Groundbreaking for the new hospital. The original brick main building was replaced with a concrete one with construction started in 1971; four remaining 1915 five-story edifices are among the tallest brick buildings in the city.
  • 1972: Trauma Center opens at Mission Emergency, with a grant from NIH.
  • 1973: Outpatient department, Stroke Research Center, coronary and respiratory ICUs, Family Practice residency starts.
  • 1976: New SFGH Medical Center opens after three years of planning by community advisory boards.
  • 1979: Specially equipped Burn Unit, San Francisco's second, becomes part of the Trauma Center; Gladstone Foundation Cardiovascular Laboratories open.
  • 1980: Ernest Gallo Clinic and Research Center established to study basic neuroscience and the effects of alcohol on the brain.
  • 1983: UCSF clinicians and researchers develop the country's first outpatient AIDS clinic and inpatient ward at SFGH.
  • 1991: Trauma Center designated the only Level I Trauma Center in San Francisco providing around the clock medical and psychiatric emergency services.
  • 1993 :The Gladstone Institute of Virology and Immunology opens at SFGH, second largest basic research institute in the US. In partnership with UCSF, conducts research on new drugs and treatment for HIV/AIDS, along with clinical trials, prevention, outreach, and professional education programs.