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Western Reserve College was the only college in northern Ohio when it was established in 1826. Its founders chose Hudson, Ohio over Cleveland so that the college would be "retired from the noise and bustle of a commercial city."

A large gift from Cleveland philanthropist Amasa Stone was destined to change this. In 1892, as a result of Stone's philanthropy, the college moved to Cleveland, already the home of the Medical Department of Western Reserve College. Stone's gift provided for the construction of two buildings (a classroom building, still standing, and a dormitory) and for an endowment fund, but carried the condition that the college be renamed in memory of his only son, Adelbert, who had drowned in 1865 while a student at Yale. The undergraduate college was named Adelbert College of Western Reserve University, becoming the only American college of its time bearing a single given name without the prefix "Saint."

Enrollment at Western Reserve College had been open to women since 1872, and the practice continued at Adelbert College. It continued, that is, until 1888, when university trustees abolished coeducation. The trustees recognized, however, that women should not be denied higher education and at the same meeting established the College for Women, Flora Stone Mather, daughter of Amasa Stone, became a lifelong supporter of the new college. With the help of Eliza Clark, Anna M. Harkness, Jeptha Wade II, and Louis H. Severance, she helped the women's college develop its own quarters across the street from Adelbert. In 1931, the college was renamed in her memory.

In 1925, another college came into being, an undergraduate college initially for adults pursuing studies part-time. It was named Cleveland College. Located on Public Square, it was the brainchild of Newton D. Baker, Secretary of War under Woodrow Wilson and mayor of Cleveland. Its teachers came from both Western Reserve University and the neighboring Case School of Applied Science, later named Case Institute of Technology. When enrollment declined in the 1950s, Cleveland College was moved to the main campus in University Circle and housed in a new building named for Baker.

Over the years a spirited rivalry developed between Western Reserve University and Case Institute of Technology, particularly in athletics. The annual Case-Reserve football game, for instance, nearly filled League Park and, later, the Cleveland Stadium on Thanksgiving Day. Increasing cooperation in academic programs and other areas finally led to a federation of the two institutions in 1967 under the name of Case Western Reserve University.

In 1972, the trustees consolidated three of the four undergraduate colleges, Adelbert, Mather, and Cleveland, into a single coeducational college. Its name had a familiar ring: Western Reserve College. This step was not as drastic as it might have appeared, since the faculties of Adelbert and Mather had been merged since 1950 and student in the two colleges had to meet identical degree requirements. Besides, other single-sex colleges by the score had become coeducational during the late 1960s and early 1970s. Western Reserve College is thus a fairly young college and at the same time one of the oldest private liberal arts colleges in the nation.

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