The University got its nickname "Ole Miss" via a contest in 1897. That same year, the student yearbook was being published for the first time. As a way to find a name for the book, a contest was held to solicit suggestions from the student body. Elma Meek, a student at the time, submitted the winning entry of Ole Miss. This sobriquet was chosen not only for the yearbook, but also became the name by which the University is now known.

The Lyceum, built in 1848, is the oldest building on campus. In its first year, it housed all of the classrooms and faculty offices of the university. The Lyceum is now the home of the university's administration offices. The columned facade of the Lyceum is represented on the official crest of the university, along with the date of establishment.

The School of Medicine, which was originally located at the eastern gate of the campus, was used as a hospital during the Civil War for both Union and Confederate soldiers, especially those who were wounded at the battle of Shiloh. The School of Medicine then teaching the first two years of pre-clinical education and granting medical certificates was moved to the western edge of campus into Billy S Guyton Hall in 1934. After the medical school moved to the new University Hospital in Jackson, Guyton Hall housed the ROTC units. After a complete renovation in 2005 it currently houses the School of Education. The School of Medicine is now located in Jackson, Mississippi. The original building, was renamed Brady Hall in honor of a former head nurse, this building served as a dormitory for male students and then as the home of the Music Department in its last years before being condemned in the early 1970s, was replaced by a new Chemistry building in the mid 1970s. Soldiers who died in the campus hospital were buried in a mass grave located at the northeast corner of the Coliseum which was built nearly 100 years later as a venue for concerts and basketball games.

With the outbreak of the Civil War, classes were interrupted when the entire student body and many faculty from Ole Miss enlisted in the Confederate army. Their company, Company A, 11th Mississippi Infantry, was nicknamed the University Grays, and suffered a 100% casualty rate during the Civil War. A great number of those casualties occurred during Pickett's Charge at the Battle of Gettysburg on July 3, 1863, when the University Grays made the deepest encroachment into Union territory. Some of the soldiers actually crossed the Union defensive fortification wall, only to be killed, wounded or captured. On the very next day, July 4, Confederate forces surrendered at Vicksburg, Mississippi; the two battles together are commonly viewed as the turning point in the war. When Ole Miss re-opened, only one member of the University Greys was able to visit the university to address the student body. The university was led, during the post-war period, by former Confederate general A.P. Stewart, a Rogersville, Tennessee native, who was President from 1874-1886.

During the 1930s, an attempt by Mississippi Governor Theodore G. Bilbo to move the University of Mississippi to Jackson, was prevented by then Chancellor Alfred Hume by giving Mississippi legislators a grand tour of Ole Miss and the surrounding city of Oxford. It so impressed the legislators that the move was defeated.

Desegregation came to Ole Miss in the early 1960s with the activities of United States Air Force veteran James Meredith from Kosciusko, Mississippi. Even Meredith's initial efforts required great courage. All involved knew how violently Dr. William David McCain and the white political establishment of Mississippi had recently reacted to similar efforts by Clyde Kennard to enroll at Mississippi Southern College (now the University of Southern Mississippi).

Meredith won a lawsuit that allowed him admission to the University of Mississippi in September 1962. He attempted to enter campus on September 20, September 25, and again on September 26, only to be blocked by Mississippi Governor Ross R. Barnett, who proclaimed that "...No school in our state will be integrated while I am your Governor. I shall do everything in my power to prevent integration in our schools."

After the United States Court of Appeals for the Fifth Circuit held both Barnett and Lieutenant Governor Paul B. Johnson, Jr. in contempt with fines of more than $10,000 for each day they refused to allow Meredith to enroll, Meredith, escorted by a force of U.S. Marshals, entered the campus on September 30, 1962.

The enrollment of Meredith led to an anti-desegregation riot. Thousands of students, citizens from the surrounding area and many from out of state, many armed, were involved. There was a sense among a certain class of white Mississippi males that this was their battle against 'Catholic, Communist, Northern' intervention in Mississippi white people's business. The protesters swarmed the campus in a violent effort to prevent Meredith's enrollment, and thus save a part of the segregationist policies of Mississippi at the time.

Two people died during the riot. Meredith, thanks to the protection afforded by federal marshals, was able to enroll and attend his first class on October 2. Following the riot, elements of an Army National Guard division were stationed in Oxford to prevent future similar violence. While most Ole Miss students did not riot prior to his official enrollment in the university, many harassed Meredith during his first two semesters on campus.