The hospital's origin can be traced to a 1769 commencement address by Samuel Bard, a graduate of the University of Edinburgh Medical School and professor of medicine, which was delivered to the first two medical doctors to graduate from King's College, now Columbia University Vagelos College of Physicians and Surgeons, titled “A discourse upon the duties of a physician, with some sentiments on the usefulness and necessity of a public hospital.” New York City leaders later pledged one thousand pounds sterling to the hospital's creation.

[8] Later the same year, on November 3, 1769, Peter Middleton reported on progress with the hospital's creation in another address to King's College, stating “the necessity and usefulness of a public infirmary has so warmly and pathetically set forth in a discourse delivered by Dr. Samuel Bard... that his Excellency, Sir Henry Moore immediately set on foot a subscription for that purpose to which himself and most of the gentlemen present liberally contributed.” [9] Soon thereafter, the new Governor of the Colony, John Murray, 4th Earl of Dunmore through the interposition of Lieutenant Governor Cadwallader Colden started a fund for the establishment of such a hospital.

"[11] The first regular meeting of the Governors after its organization was held on July 24, 1771, at Fraunces Tavern, the same location where General Washington would bid farewell to his officers on December 4, 1783.

The American Revolutionary War delayed the building's reconstruction but a partial structure on Broadway and Duane Street served as a barracks for Hessian and British Army soldiers, as a laboratory for teaching anatomy to medical students, and as a military hospital.

[14] Although initially ignored by the wider community, grave-robbing incidents in the 1780s were met with public outrage after medical students – who were taking the corpses in order to dissect them for anatomical study – turned from stealing from the "Negroes Burying Ground" to the more closely-located, and white, Trinity Churchyard.

[12] After some years of experience in treating the mentally ill, the hospital's board of governors decided to construct an additional building designed to specialize in treatment of the mentally ill. After receiving financial assistance from the New York state legislator, the governors erected "a substantial and spacious stone edifice on the grounds of the hospital in the city, within the same enclosure, and but a few rods distant from the original building.

[18] Due to real estate pressures, the hospital moved to White Plains, New York in 1891,[19] where it eventually became the Payne Whitney Psychiatric Clinic, now known as "New York-Presbyterian/Westchester".

Despite the clinical alliance, the faculty and instructional functions of the Cornell and Columbia medical school units remain largely distinct and independent.

The hospital is certified as a Level II Trauma Center and houses the only pediatric burn unit in the New York City Metropolitan Area.