The area now known as Fondren was originally home to the Mississippi Lunatic Asylum, situated at the fork where Jackson's northernmost boundaries reached Canton Road. Following the Civil War, Isham Cade, a Black man, bought a large parcel of land at the fork, subdivided it, and had it surveyed. It was known for years as 'Sylum Heights, though the original plat shows it as the Isham Cade Survey.

The first Fondren, Richard, moved from South Carolina and bought nearly 500 acres in Jackson in 1845. In 1893, two of Richard's sons, Edward Douglas and David Fulton, moved south and settled in the area that bears their name. They formed Fondren-Greaves Realty Company with their nephew, Elmore Greaves. Ed became involved in politics, serving as Hinds County tax assessor and Circuit Clerk. David continued in real estate and built a wood-frame general store at the fork between Canton Road and Tougaloo Road, well positioned to serve the community, hospital, and travelers.

The location fronted an Illinois Central rail spur serving the asylum, providing easy access for supplies and timber. In 1894, a post office was established in the Fondren Grocery. Residents petitioned the U.S. Postal Service to name the station Fondren rather than 'Sylum Heights. A Fondren post office still exists today near the original location.

In 1925, Jackson annexed Fondren as development pressures pushed housing south. It was the first inclusion of a developed community within Jackson city limits. In 1935, a new state mental hospital was built at Whitfield, and most old asylum structures were demolished. The diverse Fondren community continued without its original organizing focus.

Duling School was built in 1928, and after World War II, Mississippi's first suburban shopping center, Morgan Center, was built on the original Cade's Alley. Jackson's first "high-rise" suburban office building, the Dale building, was constructed in Fondren in 1956. The post-war boom added significantly to housing stock. The neighborhood remained racially diverse until the 1950s when rising property values forced the last Black resident from Cade's Alley.

The community continued growing with businesses, churches, drug stores, restaurants, and other amenities. The late 1930s/early 1940s "Fondren Strip" was built on North State Street.

By the 1980s, residents were abandoning the neighborhood for new suburban communities, reducing owner-occupied housing. Long-term residents organized the Fondren Renaissance Foundation, creating a private tax base and neighborhood security. Thirty rental houses were rehabilitated and resold the first year, and the state's first urban Main Street program was instituted.

The "Downtown Fondren Historic District, roughly along North State Street, Old Canton Road, Duling Avenue & Fondren Place," was named to the National Register of Historic Places on September 10, 2014.