Historically preceded by the community's Muskingum Academy, established in 1797, today's College was chartered in 1835, and the first president was the Rev. Joel H. Linsley. In the years before the Civil War, its students absorbed the city's ethic of supporting abolitionism. They helped fugitive slaves take shelter at the college, which was used as a station on the Underground Railroad to help slaves reach freedom in northern states or Canada.

Marietta College worked toward high academic achievement. In 1860, it became the sixteenth college awarded a chapter ofPhi Beta Kappa, the world's oldest honorary society.

During the Great War, before the United States entered the war, a group of students went to France to serve as the Marietta College Volunteer Ambulance Corps. After the war, France commemorated their service with what is known as the French monument, which it gave to the city of Marietta. The memorial has two parts: a replica of a historic 1749 plaque found buried at this site, which noted the French claim to the Ohio Country, and a plaque to commemorate the ambulance corps. The names of the young men who served with the corps are included.

In the 21st century, the majority of the students at the college are from Ohio, Pennsylvania and West Virginia, but a sizable portion of the student population is from the New England states, and Asia.