The city was founded in 1818 by Samuel Jayne from New York, who named it after the town of Brookhaven on Long Island.

During the Civil War, Brookhaven was briefly occupied at noon on April 29, 1863, by a raiding party of Union cavalry under the command of Colonel Benjamin Grierson.

In 1908, a mob of 2,000 White people assaulted a military guard and kidnapped a Black man, Eli Pigot, and murdered him in broad daylight.

[9] In 1955, Lamar Smith, a black farmer and World War I veteran, was shot to death by whites mid-day on the lawn of the county courthouse in Brookhaven.

[10] He had been working to organize voter registration among blacks, who had been largely disenfranchised in the state since 1890 by barriers created by whites.

US 51 runs parallel to I-55, passing through the west side of Brookhaven closer to the city center.

This so upset the black population, who felt that this was a racially-insensitive move, that a school boycott ensued, ultimately resulting in the rescission of Rutter's hiring.

The former institution of higher learning Whitworth Female College, founded in 1858, was located in Brookhaven.

[22] In 2019, it was reported that the school district still "has largely segregated classrooms – some all-black, some majority white.

"[23] Brookhaven is a part of the Jackson, Mississippi television market, including news stations WLBT, WJTV, WAPT, and WDBD.

Amtrak's famous City of New Orleans (subject of the song ballad written by Steve Goodman and recorded by folk singer Arlo Guthrie in 1972) serves Brookhaven, going north and south on the old Illinois Central and Gulf, Mobile and Ohio railroad lines.