Southaven began as a village when Memphis homebuilder Kemmons Wilson (founder of Holiday Inn) wished to develop a few residential subdivisions featuring small starter homes just across the Mississippi border from what was then Whitehaven, Tennessee, an unincorporated area just a few miles south of the Memphis city limits.

In the 1970s, Whitehaven has been eventually annexed by Memphis. Officially incorporated in 1980, Southaven is one of the fastest-growing cities in the southeastern United States. In just 20 years, Southaven doubled its land area, while its population tripled. The construction of Interstate 55 through Southaven in the 1970s helped to promote growth and make for easier access to the city from Memphis, Jackson, St.

Louis, and Chicago. Interstate 69, which will eventually run from Canada to Mexico, was cosigned with I-55 in Southaven in 2007.In 1988, Baptist Hospital-DeSoto opened in Southaven as a two-story hospital. In 2001, Baptist DeSoto started an expansion project, nearly doubling the size of the hospital.

In 2002, Baptist Hospital-DeSoto added an Outpatient Diagnostic Center and a Women's Center. In November 2006, Baptist DeSoto opened an eleven-story hospital tower that added 140 beds to the facility, allowing it to offer all private rooms. In addition, the new hospital tower added a new and expanded Emergency Department, more operating suites and space for future additions.

It is the first high-rise building constructed in DeSoto County. The exponential growth of Memphis International Airport (2 miles north of the city limits) in the 1980s led to increased air traffic over Southaven. The city continues to see large amounts of air traffic from Memphis International Airport, as flight paths to both north–south runways lead directly over the city.

October 2007 saw the opening of Southaven's first large-scale shopping mall, Southaven Towne Center, which is located just south of Goodman Road between I-55/I-69 and Airways Boulevard. The mall is open-air with various stores and restaurants, including J.C. Penney, Dillard's, Gordmans, Sportsman's Warehouse, and Bed, Bath, and Beyond.

Numerous buildings in Southaven were damaged on February 5, 2008, when an EF-2 tornado touched down during the so-called Super Tuesday tornado outbreak. Memphis television station WREG broadcast live images of the tornado as it moved through the city and into Memphis. No fatalities were reported in Southaven.

By February 2011, Southaven had become the third-largest city in Mississippi. In the late 2000s, an outlet mall was proposed for Southaven. Tanger Outlets Southaven began construction in January 2015 and opened in November 2015. The mall, located near I-55/I-69 and Church Road, includes 70 outlet stores and outparcels of restaurants.

Southaven was the boyhood home of noted novelist John Grisham, who also practiced law there for almost a decade, and of singer and songwriter Cory Branan.