The College of Pharmaceutical Sciences was founded as the College of Pharmacy of the City of New York by a group of apothecaries, physicians and wholesale drug merchants in 1829 for the education of apprentices; it was the second college of pharmacy to be organized in the United States. Instruction began in December 1829 and the first diploma was awarded in 1831.

The College had a checkered existence throughout its first fifty years. It moved frequently, suspended classes twice in the 1840s, and came close to foreclosure in 1857. The purchase of its first building in 1878, a former chapel on East 23rd Street, signaled the start of a more stable era.

In 1894, the College constructed a modern facility on West 68th Street near Columbus Avenue where it remained for the rest of its existence. In 1904, it entered into an affiliation agreement with Columbia College (Columbia University after 1912), which allowed it to retain its corporate and financial independence while issuing its degrees under Columbia's name. The College never became an integral unit of the University.

Graduate instruction began as early as 1897 and a four-year course leading to the B.S. was instituted in 1913, though shorter courses for alternate degrees remained available into the 1930s. In 1966, the institution's name was changed to the College of Pharmaceutical Sciences.

Though the post-World War II years brought relative prosperity and increased enrollment to the College, it was unable to find the funds to upgrade and expand its facilities and was placed on probation in 1967 by the American Council on Pharmaceutical Education. The College staved off further action until 1973 when the Council notified the College that it would lose its accreditation. Unable to find funding or a merger partner, the College graduated its last class in May, 1976.