In July 1754, Samuel Johnson held the first classes in a new schoolhouse adjoining Trinity Church, located on what is now lower Broadway in Manhattan. There were eight students in the class. At King's College, the future leaders of colonial society could receive an education designed to "enlarge the Mind, improve the Understanding, polish the whole Man, and qualify them to support the brightest Characters in all the elevated stations in life." One early manifestation of the institution's lofty goals was the establishment in 1767 of the first American medical school to grant the M.D. degree.

The American Revolution brought the growth of the college to a halt, forcing a suspension of instruction in 1776 that lasted for eight years. However, the institution continued to exert a significant influence on American life through the people associated with it. Among the earliest students and trustees of King's College were John Jay, the first chief justice of the United States; Alexander Hamilton, the first secretary of the treasury; Gouverneur Morris, the author of the final draft of the U.S. Constitution; and Robert R. Livingston, a member of the five-man committee that drafted the Declaration of Independence.

The college reopened in 1784 with a new name—Columbia—that embodied the patriotic fervor that had inspired the nation's quest for independence. The revitalized institution was recognizable as the descendant of its colonial ancestor, thanks to its inclination toward Anglicanism and the needs of an urban population, but there were important differences: Columbia College reflected the legacy of the Revolution in the greater economic, denominational, and geographic diversity of its new students and leaders. Cloistered campus life gave way to the more common phenomenon of day students who lived at home or lodged in the city.