In 1839, the Missouri Legislature passed the Geyer Act to fund a state university. Citizens of Columbia and Boone County pledged $117,921 in cash and land to beat five rival counties for the prize. The school initially admitted only white male students. When the Civil War forced the university to close for much of 1862, residents formed a Union home guard militia known as the 'Fighting Tigers of Columbia,' named for their readiness to protect the city. In 1890, the newly formed football team adopted the name. Union troops stationed on campus used the library in Academic Hall as a guard room, burning 467 volumes for firewood. The board of curators later sued the U.S. Army for the damage; the settlement, finally paid in 1915, funded the Memorial Gateway that still stands on the northern edge of Red Campus.

In 1908, Walter Williams founded the Missouri School of Journalism at Mizzou, establishing what claims to be the world's first school of journalism. The school operates on a 'Missouri Method' of learning by doing: students publish the daily Columbia Missourian, run NBC affiliate KOMU-TV as a full commercial station, produce Vox Magazine, and operate National Public Radio station KBIA. The journalism school has been ranked the top program in the United States multiple times. Williams himself went on to serve as university president from 1931 to 1935. The same year the journalism school opened, MU joined the Association of American Universities, a distinction it has maintained since, recognizing its status among the nation's leading research institutions.

The burned columns of Academic Hall anchor Red Campus, the historic core of brick buildings surrounding Francis Quadrangle, which is listed on the National Register of Historic Places. Jesse Hall, named for president Richard Jesse, replaced Academic Hall in 1895 and now serves as the administrative heart of the university. George Kessler designed the landscaping in 1910 in the City Beautiful style. To the east, White Campus emerged in 1913-1914 as Neo-Gothic limestone buildings for new academic programs. Memorial Union honors students lost in World War I. Memorial Stadium opened in 1926 with a capacity of 71,168, known today as 'The Zou.' The University of Missouri Research Reactor Center operates the most powerful university research reactor in the country and is the sole domestic source of isotopes used in nuclear medicine.

The university's history of racial reckoning runs deep. In 1923, a Black janitor named James T. Scott was lynched by a mob of townspeople and students near campus. In 1935, Lloyd L. Gaines, a graduate of Lincoln University in Jefferson City, was denied admission to MU's law school. His case reached the Supreme Court, which in 1938 ordered Missouri to admit him or provide an equal facility. Gaines disappeared in Chicago in 1939 under suspicious circumstances; the university granted him a posthumous honorary law degree in 2006. Undergraduate divisions were integrated by court order in 1950. A Confederate memorial erected in 1935, known as Confederate Rock, was removed in 1974. In 2015, student protests over racial issues led to the resignation of both the chancellor and the university system president.

Mizzou's alumni list reads like a cross-section of American achievement. Sam Walton founded Walmart. William W. Mayo founded the Mayo Clinic. Tennessee Williams wrote Cat on a Hot Tin Roof and A Streetcar Named Desire. Brad Pitt and Jon Hamm became Hollywood stars. Sheryl Crow built a Grammy-winning music career. George C. Scott won the Academy Award for Patton. Two Nobel laureates claim MU ties: Frederick Chapman Robbins in Physiology or Medicine in 1954, and George Smith in Chemistry in 2018. Senator Tim Kaine, journalist Jim Lehrer, astronaut Linda Godwin, and cartoonist Mort Walker all passed through Columbia. In 1911, athletic director Chester Brewer invited alumni to 'come home' for the football game against Kansas, an event claimed as the origin of the American homecoming tradition. The homecoming blood drive holds a Guinness Record as the nation's largest.