Pope County was created January 10, 1816, from parts of Gallatin and Johnson Counties and named for Nathaniel Pope, Territorial Secretary from 1809 until 1816. In 1818 the western boundary line was moved eastward to accomodate an addition to Johnson County. In 1839 the eastern part of the county was split off and, together with a piece of Gallatin County, became Hardin County. The south boundary was altered in 1843 in order to form Massac County.

The county seat, Golconda, was founded in 1798 and chartered in 1816. The town was first named Sarahsville, after Sarah Lusk, widow of Major Lusk who had established a ferry there in 1797. After the death of Major Lusk in 1803, Sarah applied for and was given the license to operate the ferry by William Henry Harrison, Governor of Indiana Territory. She operated the ferry until her marriage to Thomas Ferguson in 1805, who then took over the operation.

The first county courthouse was begun in 1817 and completed in 1820. The present courthouse was begun in 1872 and finished in 1873.

The first settlers were Scots-Irish from the southeastern states. They were soon joined by many others, including a large community of German immigrants who retained the language and conducted church services in German.

Today much of Pope County is covered by the Shawnee National Forest. Every fall the population of the county swells by thousands of visitors during the annual Deer Festival. The November festival coincides with the first Illinois deer season each year.