By 1858, Cane Hill College had expanded in size to four buildings, including a dormitory and a two-story brick teaching facility. The school was establishing itself as a bastion of educational strength on the frontier when the Civil War brought this progress to an abrupt halt.
The College closed in 1861 when the majority of its students (at that time all male) took up arms. Almost all of the Cane Hill community was burned in 1864 when Union troops occupied Northwest Arkansas, including three of the four buildings at the college. One of the few buildings in Cane Hill to survive the destruction was the college dormitory, which was used as a hospital for Union troops under the command of Brigadier General James G. Blunt.
Classes resumed soon after the war, and in 1868 the College added another frame structure to the campus. In 1875 Cane Hill College made another bold step when it became the first four-year college in Arkansas to admit women to its degree program. Formal educational opportunities had been made available to women at Cane Hill since the late 1830's, but, in keeping with the times, they were taught only the basics in English and Mathematics, and a few other courses in "Moral and Mental Science," drawing, embroidery and painting. By 1875, educational opportunities for women at Cane Hill had evolved into the Female Seminary, a virtual college empowered to grant baccalaureate degrees to women. The Female Seminary merged with Cane Hill College in 1875 and became the "Female Department" of the College. The Female Department soon disappeared and the College became truly coeducational, granting five degrees to women in the 1877 graduating class.
Seven years after this progressive change, the College suffered a major setback. On the night of October 10, 1885, the College was burned to the ground. Although the townspeople suspected arson, no one was ever apprehended. After the fire, classes were held in the Methodist Church facilities at Cane Hill. By 1886, a new brick building was constructed to house classrooms for the college, but the College would not benefit long from this construction.
In 1871, Arkansas Industrial University (better known today as The University of Arkansas) had received a state charter for its campus in Fayetteville, about 20 miles northeast of Cane Hill. While this single event hadn't impacted the small community of Cane Hill as dramatically as the war had, it was now proving to be much more devastating to Cane Hill College.
For years, Fayetteville had been outstripping Cane Hill as a population and commercial center, giving Arkansas Industrial University a much broader student base. Cane Hill College was woefully short of financial assistance. Although the 1852 charter provided for support of the College by the Arkansas Synod of the Cumberland Presbyterian Church, Synod support was negligible at best and often nonexistent. For the most part, the Cane Hill congregation alone had borne the burden of support for the College. The competition and financial strain finally grew too great for the small, private College to continue, and in 1891 it closed its doors as Cane Hill College for the last time.