In 1836, a few miles from the current city of Walla Walla, Marcus Whitman and his wife Narcissa established a medical mission and a school to serve the Cayuse Indians and immigrants on the Oregon Trail. After Indians killed the Whitmans 1847, Rev. Cushing Eells resolved to establish a school in the Whitmans' honor. The Washington Territorial Legislature granted a charter to Whitman Seminary on December 20, 1859. On November 28, 1883, the legislature issued a new charter, changing the seminary into a four-year, degree-granting college.

From its beginning, Whitman College has prized its independence from sectarian and political control. Whitman has remained small in order to facilitate the close faculty-student interaction that is essential to exceptional higher education. In 1913, Whitman became the first college or university in the nation to require undergraduate students to complete comprehensive oral and written examinations in their major fields. The installation of a Phi Beta Kappa chapter in 1919, the first for any Northwest college, marked Whitman's growing reputation.