[6] It opened in 1811 with 15 students, as a preparatory school, under the name of the Washington Academy—a one-room, wood-frame structure, built on the college property.

[9] Following World War II, declining student enrollment, low tuition, and lack of external funding caused financial hardship for Jefferson College.

In 1965, all buildings and lands owned by Jefferson College were conveyed to the State of Mississippi in exchange for discharging the school's debts.

[5] Three buildings, constructed during the 19th century, are contributing resources for the Jefferson College National Historic District:[10] The old Jefferson College campus includes five other historic buildings constructed during the 19th and early 20th centuries: In January 1807, former territorial secretary and temporarily acting Governor of the Mississippi Territory, Cowles Mead (1776-1844), suspected that former Vice President Aaron Burr (1756-1836, served 1801-1805 in first Jefferson presidential administration) of a conspiracy to separate the new Old Southwest Territories (recently acquired from Spanish colonial claims) of Mississippi and adjacent Orleans Territories (later State of Louisiana), along the Mississippi River and the port city of New Orleans from the United States and ordered the Mississippi territorial militia to capture Burr to stand trial for treason.

In February 1807, a grand jury convened in the territorial capital on the grounds of Jefferson College and after investigation and a hearing, found the ex-Vice President Burr not guilty of any crime or misdemeanor against the United States.

[20] Between July 7 and August 17, 1817, the Mississippi Statehood Convention was held in a Methodist church on property adjacent to Jefferson College.

[24] Jefferson College was a location site for several commercial Hollywood theatrical motion pictures and television films / mini-series:[7][5][25][26]