The first white men to visit the area were French fur traders, who passed up the Missouri River during the first quarter of the 18th century. By 1764 French trade was well established upon the Missouri River and the eastern part of present-day Atchison County was well known to them.
Lewis and Clark passed along the eastern boundary on their expedition in 1804 and spent some time in exploring the banks of the Missouri River. In 1818 the first military post established by the United States government in what is now Kansas was built on the Isle au Vache, or Cow island. It was known as Cantonment Martin.
In 1833 the Kickapoo Indians entered into a treaty with the federal government and the Kickapoo Reserve was established most of the county, with the exception of the southwest corner which was a part of the Delaware Reserve, established by a treaty in 1831.