Guadalupe College was a private Baptist college for African Americans in Seguin, Texas. It was established in 1884 and opened officially in 1887. Its founding was chiefly due to the efforts of William B. Ball, who later became its president. David Abner Jr. was president of Guadalupe College from 1891 to 1906, a 15-year tenure during which the college flourished and gained statewide recognition. At its height during his administration, the college had an enrollment of approximately 500 students.

Guadalupe College offered a traditional liberal arts program based on classical courses, as well as an "academy" and grammar school, but comparatively little agricultural or trades-based education. It was recognized as a junior college by the Texas Department of Education in 1926 and briefly attained senior college status, from 1929 to 1931, before being adversely affected by the Great Depression. Guadalupe College's main building was destroyed by a fire in 1936 and the college became defunct in 1937 after a fundraising drive was cancelled. Numerous later attempts to reestablish the college were unsuccessful.

Guadalupe College was established in 1884 by members of the Guadalupe Baptist Association in Seguin, Texas. The association was led chiefly by Dr. William B. Ball, an African American Civil War veteran, minister, and academic from Ohio, and Rev. Leonard Ilsley, a white preacher. Ball, the founder of the college, was a member of both the 24th Infantry Regiment and 28th Infantry Regiment of the United States Army, in which he served for three years during the American Indian Wars. In 1884, the Guadalupe Baptist Association purchased a large plot of land for $6,500, which was the site of many schools previously and is currently home to Joe F. Saegert Middle School.

In 1887, Guadalupe College's first official session was opened with J. H. Garnett serving as president. Enrollment for the first 12 years averaged over 200 students annually. On March 28, 1888, the State of Texas granted a charter to the college. Its goal was to provide the African American community with an education comparable to white institutions of the day. This curriculum at Guadalupe College consisted of four years of classical courses, which led to a bachelor of arts degree through the college department. Additionally, students could receive training and certification through five other departments: industrial, musical, preparatory, primary, and theological. Guadalupe College's early funding came from grassroots efforts of the African American community, principally donating through their churches. Additionally, philanthropist George W. Brackenridge donated considerably to the college, including giving it funds for a new chapel-auditorium and a valuable 216-acre (87 ha) tract on the Guadalupe River west of Seguin.

Garnett was succeeded by David Abner Jr. in 1891, marking the beginning of Abner's 15-year tenure, during which the college flourished and gained statewide recognition. During this time, attendance ranged from 300–500 students annually. Abner was the first African American to graduate from a Texas institution of higher learning. Before becoming president of Guadalupe College, he was a professor at the Baptist Home Mission Society of New York and was a delegate for Louisville, Kentucky's National Convention of Black Men. Due to his large success with the college, Abner received many offers from northern institutions. These positions reportedly offered much higher status and pay, but Abner declined them all and is quoted saying, "I am a southern man, conducting a school for the colored youths of the south and expect to remain right where I am."

In 1906, Abner resigned under pressure from the college's trustees. His successor as president, William B. Ball, entered a challenging period at Guadalupe College defined by "lawsuits, financial crises, declining enrollment, and loss of state endorsement". He served as president until 1913. By 1917, Ball had been named president emeritus of the college, with a contemporary issue of the El Paso Herald observing he was "the only negro in the world holding such title". As president emeritus, Ball earned a monthly salary of $60 until his death in 1923.

In 1914, George Brackenridge purchased the college and saved it "from financial ruin". He and the college's boosters moved it to farmland on the Guadalupe River in 1914, where two new brick buildings were built for the college: a four-story combined classroom and women's dormitory building and a three-story men's dormitory. In November 1914, William Henry Moses of Tennessee became the college's new president. Guadalupe College's traditional liberal arts program was retained alongside an "academy" and grammar school, with comparatively little agricultural or trades-based education. During this period college students were required to provide "evidence of good moral character", attend Sunday school and weekly prayer meetings, and work for the college on a daily basis.

In 1916, Marlin native Jesse Washington was named president. During his tenure, he created a bachelor of arts and science degree and organized the college's curriculum into nine divisions.