[4] Hunting also contributes to the economy; Mississippi's two most recent records for the heaviest alligator taken by a hunter have both been in Issaquena County, the latest in 2012 when a 697.5 lb (316.4 kg) alligator was killed at a camp near Fitler.

The first county seat was located in Skipwith, and then moved to Duncansby (both communities are now ghost towns).

[8] The county lies entirely in the Mississippi Alluvial Plain, and hardwood forest known as "bottomland" grows thick in the nutrient-rich, high-clay "buckshot" soil.

About that same time, the Louisville, New Orleans and Texas Railway was completed along a north–south route through the center of the county.

[10] In 1860,[11] 92.5% of Issaquena County's total population were enslaved people, the highest concentration anywhere in the United States.

[13] Stephen Duncan of Issaquena County held 858 slaves, second only to Joshua John Ward of South Carolina.

[15] During the winter of 1862 and spring of 1863, Union Army General Ulysses S. Grant conducted a series of amphibious operations aimed at capturing the Confederate stronghold of Vicksburg, located south of Issaquena County.

[16] The shallow waterways proved difficult for the large Union boats, and Confederate defenses were robust.

The Steele's Bayou Expedition was a defeat for Union forces in Issaquena County.

[17] In 1971, a large and long-tracked tornado destroyed multiple towns in Issaquena County.

However, the county voted for Republican senator Thad Cochran's reelection bid in 2014.

Students attend campuses in neighboring Sharkey and Washington counties.