Historic American Indian tribes in the area included the Muskogean-speaking Creek, Choctaw, and Alabama, who had inhabited the lands for centuries and had many settlements. The former two tribes were among those in the Southeast whom the European-American settlers called the Five Civilized Tribes, as they adopted some European-American cultural ways in an attempt to survive alongside the encroachment of settlers moving into the area in the early nineteenth century. Most of these peoples were removed by United States forces in the 1830s to Indian Territory west of the Mississippi River.
The state made land grants to European Americans, who developed the land as large cotton plantations, based on slave labor by African Americans. Some Creek remained in the area. At the time, they were required to renounce their tribal membership and were granted US and state citizenship. They continued to live as a community and to maintain ties. In the twentieth century, the Poarch Band of Creek Indians was recognized as a tribe, established a government under a written constitution, and have certain lands that were taken into trust by the federal government. They have established three gaming resorts to generate revenues for tribal health and welfare.
Escambia County was organized and established after the American Civil War, on December 10, 1868 during the Reconstruction era. The state legislature created it from parts of Baldwin and Conecuh counties, to the west and north, respectively. The area was part of the coastal plain. It was largely agricultural into the twentieth century.
The county is subject to heavy winds and rains due to seasonal hurricanes. In September 1979, the county was declared a disaster area due to damage from Hurricane Frederic. It was declared a disaster area again in September 2004 due to damage from Hurricane Ivan.