When Florida became a territory in 1821, Andrew Jackson was appointed Governor and among his first duties, he subdivided the state into two counties - East Florida and West Florida. After several other divisions had taken place, on June 24, 1823, a fifth county generally spoken of as Middle Florida was established. Boundaries for the new county were the Suwannee on the east and the Apalachicola River on the west and it was named Gadsden in honor of James Gadsden, aide-de-camp to General Andrew Jackson in the Florida Campaign of 1818.

Pensacola was the scene for the first Legislative Council and Jacksonville, the site for the second. These two sessions, two years and miles apart in hardship and distance, convinced the Council of the need for a central location. Two commissioners, Dr. William Hayne Simmons and John Lee Williams were selected to explore a possible site in Middle Florida. By March 4, 1824, these two commissioners reported they had chosen an area in Gadsden County, "about a mile southwest from the deserted fields of Tallahassee Indians Village about a mile south of the Oke-lock-o-ny and Tallahassee trails"

Gadsden County citizens played important roles in the capital city building project. The temporary capital was erected in April 1824 by Jonathan Robinson and Sherod McCall. Their building was actually one of three log buildings constructed to accommodate the Legislative Council which met November 8 of that year. The capital remained in Gadsden County until December 29, 1824 when one of the first legislative acts that year was to create a new county (Leon) by annexing all the lands of East Gadsden between the Ocklochonee and Suwannee Rivers which, without moving the structures, moved the capital to Leon County.

Gadsden County is often associated with shade tobacco, Fuller's Earth and Coca Cola. Shade tobacco was the county's first big industry. Only two places in the United States were suitable for the growing of this crop which was used to wrap cigars; the "Georgia-Florida Shade Tobacco District" comprised of Gadsden and Madison counties in Florida and Grady and Decatur counties in Georgia and the Connecticut River valley in New England. In 1946, these two districts were producing over 95% of American-grown wrapper leaf and they represented a $100,000,000.00 industry of which $25,000,000.00 was invested in land equipment, barns, packing houses, and operating capital in the Georgia-Florida area. Total acreage devoted to the plants ranged from 6072 at the peak to 344 in 1977. Today shade tobacco is grown only in the Connecticut River valley and the shade tobacco barns are most often seen in paintings and photographs as few are still standing. One of the by-products of the shade tobacco era which still thrives is agricultural research. In 1929, the Legislature, impressed with the tobacco research, agreed to expand the research to other agricultural endeavors. During that year, 617 acres located 3.5 miles from Quincy was acquired to expand the tobacco research and to initiate general field crops and livestock investigations. Plant nurseries have taken the place of shade tobacco as the leading agricultural industry in the county.