The first charter of the College of Physicians & Surgeons, granted by the New York State Board of Regents on March 12, 1807, vested governance of the institution in all the members of the Medical Society of the County of New York. It was quickly realized that this was impracticable and an amendment of March 3, 1808 required Medical Society members interested in serving as Trustees to declare in writing their acceptance of the duties required in governing the school.

It was not until 1811, however, that an amendment to the charter created a Board of Trustees distinct and separate from the membership of the Medical Society. The charter specified a Board of no more than 25 members of which the president, vice-president, treasurer, and professors of the College of Physicians & Surgeons were always to be members. In practical terms, this meant that faculty had a decisive majority on the Board, which created considerable dissension in New York medical circles. To rectify the situation, the State Legislature in 1826 amended the charter to require that there always be at least 13 Trustees who were not members of the medical profession. Although the immediate effect of this change was a mass resignation of the faculty, in the long run it stabilized the College after two decades of intermittent controversy and remained a requirement for the remainder of the College's existence as an independent corporation.

At its inception the P&S Trustees were answerable to the New York State Board of Regents, a group created by the State Legislature in the 1780s to control all higher education in New York. During the course of the 19th century this function of the Regents became obsolete as colleges received charters directly from the State Legislature. Besides this, the many inconveniences related to being answerable to an agency in Albany led P&S in 1860 to severe its ties with the Regents and forge an affiliation with Columbia College. The alliance was a purely nominal one, however, with P&S retaining its independence both financially and educationally. The agreement required that the President of Columbia be guaranteed a seat on the P&S Board of Trustees and preside with the President of P&S at commencement. In addition, P&S issued its diplomas as the "medical department of Columbia College."

The P&S Board of Trustees went out of existence in 1891 as a result of the complete merger of school into Columbia College.