It was founded as Christian University in 1853 as the first institution west of the Mississippi River chartered specifically for men and women.

In the 1850s, Pat Henderson and other Christian Church (Disciples of Christ) leaders were interested in creating an institution for the education of male and female students.

Describing the site of the college that he had helped to select, Henderson said:[4] Here on the summit of two of a circle of hills, divided by a vale so virgin in its primitive luxuriance of forest and tangled wood that twilight lingers at midday beneath its bough, are to arise the structures dedicated to the equal culture of the male and female mind.

[5] In 1853, the college's founders were granted a charter by the State of Missouri to establish Christian University, in which classes began in 1855.

Christian University was the United States' first co-educational institution of higher learning west of the Mississippi River.

[4] After a local scuffle between Southern and Northern sympathizers, federal troops were sent to Canton in July 1861 where they occupied the school's only building.

They occupied it until early December 1862, using the building as a base for expeditions to fight Confederate units, chase down deserters, and seize property of disloyal citizens.

They left Old Main a ghostly shell with broken doors and windows and locks, burned seats, and much of the furniture and teaching materials carried off or destroyed.

Under the leadership of B. H. Smith, the college reopened in 1865, but made little financial and physical progress until Carl Johann became president in 1902.

College President Carl Johann resolved to rebuild; and within 10 days of the fire, the citizens of Canton raised $15,000 for a new building.

Styled in the Neo-Classical manner, the building is dominated by a colossal, tetrastyle Ionic portico and crowned by a dome.

Henderson Hall originally housed science laboratories, men's and women's gymnasiums, a museum, a dining room, a "commercial" department, library, administrative offices, classrooms, an assembly hall that seated about 600 with a rolling door at the rear that could be opened to add 400 more spectators, and three meeting rooms for student groups.

The hall represents an early collaboration between important pioneer donors, Mary Culver and Robert Stockton, each of whom contributed $25,000.

The dormitory wings of Johnson burned in a spectacular fire on the night of Jan. 9, 1924, but they were rebuilt to house 100 women.

Student rooms were improved, and plush carpet, new lighting and furniture was added to the lounge.

[14] The college library had been housed in Henderson Hall until 1947, when the need for a separate library/classroom building became acute.

[15] The first football game was played in Poulton Stadium on Sept. 18, 1948, when Monmouth College defeated the Wildcats 12–6.

Roy D. Wilcox Memorial Pressbox, named in honor of a C-SC alum, was added in 2003, replacing the original one-room press box built in 1953.

Voluntary chapel service continued reflecting the historic affiliation with the Christian Church (Disciples of Christ) and the mission of the college.

Services were held in an assortment of places including an outdoor chapel on the northeast corner of campus.

[16] Connected to the east wing is the Carla Rifkind Warsaw Memorial Chapel of All Faiths.

Long-time art professor, Grant Kenner created the All Faiths Frieze encircling the chapel interior in 1973–1976.

The frieze displays an original ecumenical emblem designed by Prof. Kenner and 44 other symbols representing the great religions of the world.

The facility houses the college's science, mathematics and computer information systems academic departments.

At the base of the hill was placed a memorial with the names of those alumni who had given their lives in World War II.

[27] Culver–Stockton College previously had a campus radio station, KCSW-LP 97.1, whose broadcast license expired in 2021.