Lee County is part of the Fort Madison–Keokuk, IA–IL–MO Micropolitan Statistical Area.

Lee County was the location of the Half-Breed Tract, established by treaty in 1824.

[citation needed] Lee County as a named entity was formed on December 7, 1836, under the jurisdiction of Wisconsin Territory.

[2] Large-scale European-American settlement in the area began in 1839, after Congress allowed owners to sell land individually.

[citation needed] Members of the Church of Jesus Christ of Latter-day Saints (LDS Church) under the direction of Brigham Young fled persecutions in Missouri to settle in Illinois and Iowa.

Nauvoo, across the border in Hancock County, Illinois, became the main center of Latter-day Saints settlement, but there was also a Latter Day Saints stake organized in Lee County under the direction of John Smith, the uncle of Joseph Smith, land that was sold to them by Isaac Galland in 1839.

It has been variously proposed that the county was named for Marsh, Delevan & Lee, of Albany, New York, and the 'New York Land Company', who owned extensive interests in the Half-Breed Tract in the 1830s; Robert E. Lee, who surveyed the Des Moines Rapids; or Albert Lea, who helped explore the interior of Iowa.

The population ranking of the following table is based on the 2020 census of Lee County.

In 2016 however, the county swung hard to vote for Republican Donald Trump by a wide margin, a swing of over 31 points compared to 2012.