In the Antebellum era, the land on which the campus was built was owned by
David McGavock, the brother of Randal McGavock, the mayor of Nashville from 1824 to 1825 who owned the Carnton plantation.
In 1866, six months after the end of the American Civil War, leaders of the northern American Missionary Association (AMA) – John Ogden, Reverend Erastus Milo Cravath, field secretary; and Reverend Edward Parmelee Smith – founded the Fisk Free Colored School, for the education of freedmen. AMA support meant the organization tried to use its sources across the country to aid education for freedmen. Enrollment jumped from 200 to 900 in the first several months of the school, indicating freedmen's strong desire for education, with ages of students ranging from seven to seventy. The school was named in honor of General Clinton B. Fisk of the Tennessee Freedmen's Bureau, who made unused barracks available to the school, as well as establishing the first free schools for white and black children in Tennessee. In addition, he endowed Fisk with a total of $30,000. The American Missionary Association's work was supported by the United Church of Christ, which retains an affiliation with the university. Fisk opened to classes on January 9, 1866.
With Tennessee's passage of legislation to support public education, leaders saw a need for training teachers, and Fisk University was incorporated as a normal school for college training in August 1867. James Dallas Burrus, John Houston Burrus, Virginia E. Walker, and America W. Robinson were the first four students to enroll at Fisk in 1867 and upon graduation Broughton and the two Burrus' were the first African Americans to graduate from a liberal arts college south of the Mason–Dixon line. Robinson graduated as well and became a member of the Fisk Jubilee Singers. Walker became a noted missionary while the Burrus brothers were both prominent educators and, during their careers, professors at Fisk. Cravath organized the College Department and the Mozart Society, the first musical organization in Tennessee. Rising enrollment added to the needs of the university. In 1870 Adam Knight Spence became principal of the Fisk Normal School. To raise money for the school's education initiatives, his wife Catherine Mackie Spence traveled throughout the United States to set up mission Sunday schools in support of Fisk students, organizing endowments through the AMA. With a strong interest in religion and the arts, Adam Spence supported the start of a student choir. In 1871 the student choir went on a fund-raising tour in Europe; they were the start of the Fisk Jubilee Singers. They toured to raise funds to build the first building for the education of freedmen. They raised nearly $50,000 and funded construction of the renowned Jubilee Hall, now a designated National Historic Landmark. When the American Missionary Association declined to assume the financial responsibility of the Jubilee Singers, Professor George L. White, Treasurer of the University, took the responsibility upon himself and started North in 1871 with his troupe. On April 12, 1873, the Jubilee Singers sailed for England where they sang before a fashionable audience in the presence of the Queen, who expressed her gratification at the performance.
During the 1880s Fisk had an active building program, as well as expanding its curriculum offerings. By the turn of the 20th century, it added black teachers and staff to the university, and a second generation of free blacks entered classes.
From 1915 to 1925, Fayette Avery McKenzie was President of Fisk. McKenzie's tenure, before and after World War I, was during a turbulent period in American history. In spite of many challenges, McKenzie developed Fisk as the premier all Black university in the United States, secured Fisk’s academic recognition as a standard college by the Carnegie Foundation, Columbia University and the University of Chicago, raised a $1 million endowment fund to ensure quality faculty and laid a foundation for Fisk’s accreditation and future success. McKenzie was eventually forced to resign when his strict policies on dress code, extracurricular activities and other aspects of student life led to student protests.
In 1947 Fisk heralded its first African-American president with the arrival of Charles Spurgeon Johnson. Johnson was a premier sociologist, a scholar who had been the editor of Opportunity magazine, a noted periodical of the Harlem Renaissance.
In 1952, Fisk was the first predominantly black college to earn a Phi Beta Kappa charter. Organized as the Delta of Tennessee Chapter of the Phi Beta Kappa National Honor Society that December, the chapter inducted its first student members on April 4, 1953.
On April 8, 1967, a riot occurred on the college campuses of Fisk University and Tennessee State University after Stokely Carmichael spoke at Vanderbilt University. Although it was viewed as a "race riot", it had classist characteristics.
From 2004 to 2013, Fisk was directed by its 14th president, the Honorable Hazel O'Leary, former Secretary of Energy under President Bill Clinton. She was the second woman to serve as president of the university. On June 25, 2008, Fisk announced that it had successfully raised $4 million during the fiscal year ending June 30. It ended nine years of budget deficits and qualified for a Mellon Foundation challenge grant. However, Fisk still faced significant financial hardship, and said that it may need to close its doors unless its finances improve.
H. James Williams, served as president from February 2013 to September 2015. Williams had previously been dean of the Seidman College of Business at Grand Valley State University in Michigan and, before that, an accounting professor at Georgetown University, Florida A&M and Texas Southern University. Williams stepped down in September 2015. Williams was replaced by interim president, board member, Frank Sims. The interregnum concluded March 2017 when the Fisk board of trustees announced that Kevin Rome would be Fisk university's next president.