Hamilton began in 1793 as the Hamilton-Oneida Academy, and was chartered as Hamilton College in 1812. The college was founded by Samuel Kirkland as part of missions work with the Oneida tribe. The college is named for Alexander Hamilton, who was a member of the first Board of Trustees of the Hamilton-Oneida Academy.

In 1978, the all-male Hamilton College merged with the all-female Kirkland College, which had been located adjacent to Hamilton. The primary public reason for the merger was Kirkland's imminent insolvency. This merger was not done lightly, overnight or without loud dissention by some; including large student protests on campus and their occupation of the President's Building for a few hours. Today, the original Hamilton campus is referred to by students and some school literature as the "light side" or the "Stryker Campus" after its former president, Melancthon Woolsey Stryker  (or incorrectly "Striker Campus"). On the other side of the street separating the two campuses, the former Kirkland campus is referred to as the "dark side" (a reference to the lighting in the Kirkland College buildings).

Hamilton College is the third oldest college established in New York.