Southern Research was founded in Birmingham, Alabama, on October 11, 1941,  by Thomas Martin as the Alabama Research Institute.
Although Martin was named chairman of the newly chartered organization in December, 1941, activities were put on hold in the aftermath of the attack on Pearl Harbor and the beginning of US involvement in World War II. Two years later, in December 1943, with a promise of support from the Alabama Power Company, Martin reengaged the Alabama's industrial leaders and received over $100,000 in philanthropic donations.
Alabama Power Company pledged an additional US$15,000 per year for five years, $75,000 total, and this was enough for the organization to finance laboratory space and hire researchers and staff. The following year, 1944, the decision was made to change the institute's name from Alabama Research Institute, to Southern Research Institute.
Around this same time, Southern Research Institute hired its first director, Wilbur Lazier. Though he only stayed in this role for four years, Lazier is credited with recruiting many figures that shaped the history of the organization, including Howard E. Skipper.
Southern Research celebrated its 75th anniversary in October 2016. In celebration of this milestone the director of National Institutes of Health (NIH), Francis Collins, produced a video congratulating the organization on its anniversary.